Modulation of Gene Expression in Key Survival Pathways During Daily Torpor in the Gray Mouse Lemur, Microcebus murinus.

PubMed

Biggar, Kyle K; Wu, Cheng-Wei; Tessier, Shannon N; Zhang, Jing; Pifferi, Fabien; Perret, Martine; Storey, Kenneth B

2015-04-01

A variety of mammals employ torpor as an energy-saving strategy in environments of marginal or severe stress either on a daily basis during their inactive period or on a seasonal basis during prolonged multi-day hibernation. Recently, a few Madagascar lemur species have been identified as the only primates that exhibit torpor; one of these is the gray mouse lemur (Microcebus murinus). To explore the regulatory mechanisms that underlie daily torpor in a primate, we analyzed the expression of 28 selected genes that represent crucial survival pathways known to be involved in squirrel and bat hibernation. Array-based real-time PCR was used to compare gene expression in control (aroused) versus torpid lemurs in five tissues including the liver, kidney, skeletal muscle, heart, and brown adipose tissue. Significant differences in gene expression during torpor were revealed among genes involved in glycolysis, fatty acid metabolism, antioxidant defense, apoptosis, hypoxia signaling, and protein protection. The results showed upregulation of select genes primarily in liver and brown adipose tissue. For instance, both tissues showed elevated gene expression of peroxisome proliferator activated receptor gamma (ppargc), ferritin (fth1), and protein chaperones during torpor. Overall, the data show that the expression of only a few genes changed during lemur daily torpor, as compared with the broader expression changes reported for hibernation in ground squirrels. These results provide an indication that the alterations in gene expression required for torpor in lemurs are not as extensive as those needed for winter hibernation in squirrel models. However, identification of crucial genes with altered expression that support lemur torpor provides key targets to be explored and manipulated toward a goal of translational applications of inducible torpor as a treatment option in human biomedicine. Copyright © 2015. Production and hosting by Elsevier Ltd.

A New Species of Sucking Louse (Phthiraptera: Anoplura: Polyplacidae) From the Gray Mouse Lemur, Microcebus murinus (Primates: Cheirogaleidae), in Madagascar.

PubMed

Durden, Lance A; Kessler, Sharon E; Radespiel, Ute; Zimmermann, Elke; Hasiniaina, Alida F; Zohdy, Sarah

2018-04-12

Lemurpediculus madagascariensis sp. nov. (Phthiraptera: Anoplura: Polyplacidae) is described from the Gray Mouse lemur, Microcebus murinus (J. F. Miller) (Primates: Cheirogaleidae), from Ankarafantsika National Park, Madagascar. Lemurs were trapped using Sherman Live Traps and visually inspected for lice, which were preserved in 90% ethanol. Adults of both sexes and the third-instar nymph of the new species are illustrated and distinguished from the four previously known species of Lemurpediculus: L. verruculosus (Ward); L. petterorum Paulian; L. claytoni Durden, Blanco, and Seabolt; and L. robbinsi Durden, Blanco, and Seabolt. It is not known if the new species of louse is a vector of any pathogens or parasites.

The minimum alveolar concentration of sevoflurane in ring-tailed lemurs (Lemur catta) and aye-ayes (Daubentonia madagascariensis).

PubMed

Chinnadurai, Sathya K; Williams, Cathy

2016-01-01

To determine the minimum alveolar concentration (MAC) of sevoflurane for ring-tailed lemurs (Lemur catta) and aye-ayes (Daubentonia madagascariensis). Prospective experimental trial. Six adult ring-tailed lemurs, aged 1.3-11.2 years (median age: 8.26) and weighing a mean ± standard deviation (SD) of 2283 ± 254 g. Five adult aye-ayes, aged 4.4-19.3 years (median age: 8.0) and weighing 2712 ± 191 g. Minimum alveolar concentration of sevoflurane was determined using a tail-clamp stimulus. The end-tidal sevoflurane (Fe'Sevo) concentration was increased or decreased by approximately 10% after a positive or negative response to tail clamping, respectively. This procedure was repeated until a positive and negative result were seen on two consecutive trials (i.e. a negative result was achieved and a single 10% decrease in Fe'Sevo concentration resulted in a positive test). The MAC for that animal was determined to be the mean of the concentrations at the two consecutive trials. The mean ± SD MAC of sevoflurane for ring-tailed lemurs was 3.48 ± 0.55% and 1.84 ± 0.17 for aye-ayes. This represents a 47.1% higher MAC in ring-tailed lemurs compared to aye-ayes. The sevoflurane MAC was significantly higher in ring-tailed lemurs, compared to aye-ayes. The MAC of sevoflurane in aye-ayes is consistent with reported MAC values in other species. Extrapolation of sevoflurane anesthetic dose between different species of lemurs could lead to significant errors in anesthetic dosing. © 2015 Association of Veterinary Anaesthetists and the American College of Veterinary Anesthesia and Analgesia.

First insights into the social organisation of Goodman's mouse lemur (Microcebus lehilahytsara)--testing predictions from socio-ecological hypotheses in the Masoala hall of Zurich Zoo.

PubMed

Jürges, Vivian; Kitzler, Johanne; Zingg, Robert; Radespiel, Ute

2013-01-01

Following current socio-ecological hypotheses, the social organisation of a species is mainly determined by resource quality and distribution. In the case of Microcebus spp., a taxon-specific socio-ecological model was formulated earlier to explain their variable social organisation. The aim of this study was to test predictions from this model in Goodman's mouse lemur based on a data set from animals living in the semi-free colony of Zurich Zoo. During a 2-month study, we observed 5 females and 5 males using radiotelemetry. We collected data on space use and social behaviour, on sleeping sites and on sleeping group composition. Predictions were only partly confirmed. As expected, Goodman's mouse lemurs were solitary foragers with an increased level of sociality due to crowding effects at the feeding stations. In contrast to the prediction, females and males formed unisexual sleeping groups, which were stable in females and of a fission-fusion type in males. Whereas the formation of sleeping groups by both sexes may be triggered by thermoregulatory benefits, the formation of unisexual sleeping groups may result from divergent interests of the sexes. We conclude that the existing model for the evolution of mouse lemur social organisation needs to be refined. Copyright © 2013 S. Karger AG, Basel.

Long-chain n-3 PUFAs from fish oil enhance resting state brain glucose utilization and reduce anxiety in an adult nonhuman primate, the grey mouse lemur

PubMed Central

Pifferi, Fabien; Dorieux, Olène; Castellano, Christian-Alexandre; Croteau, Etienne; Masson, Marie; Guillermier, Martine; Van Camp, Nadja; Guesnet, Philippe; Alessandri, Jean-Marc; Cunnane, Stephen; Dhenain, Marc; Aujard, Fabienne

2015-01-01

Decreased brain content of DHA, the most abundant long-chain n-3 polyunsaturated fatty acid (n-3 LCPUFA) in the brain, is accompanied by severe neurosensorial impairments linked to impaired neurotransmission and impaired brain glucose utilization. In the present study, we hypothesized that increasing n-3 LCPUFA intake at an early age may help to prevent or correct the glucose hypometabolism observed during aging and age-related cognitive decline. The effects of 12 months’ supplementation with n-3 LCPUFA on brain glucose utilization assessed by positron emission tomography was tested in young adult mouse lemurs (Microcebus murinus). Cognitive function was tested in parallel in the same animals. Lemurs supplemented with n-3 LCPUFA had higher brain glucose uptake and cerebral metabolic rate of glucose compared with controls in all brain regions. The n-3 LCPUFA-supplemented animals also had higher exploratory activity in an open-field task and lower evidence of anxiety in the Barnes maze.jlr Our results demonstrate for the first time in a nonhuman primate that n-3 LCPUFA supplementation increases brain glucose uptake and metabolism and concomitantly reduces anxiety. PMID:26063461

Long-chain n-3 PUFAs from fish oil enhance resting state brain glucose utilization and reduce anxiety in an adult nonhuman primate, the grey mouse lemur.

PubMed

Pifferi, Fabien; Dorieux, Olène; Castellano, Christian-Alexandre; Croteau, Etienne; Masson, Marie; Guillermier, Martine; Van Camp, Nadja; Guesnet, Philippe; Alessandri, Jean-Marc; Cunnane, Stephen; Dhenain, Marc; Aujard, Fabienne

2015-08-01

Decreased brain content of DHA, the most abundant long-chain n-3 polyunsaturated fatty acid (n-3 LCPUFA) in the brain, is accompanied by severe neurosensorial impairments linked to impaired neurotransmission and impaired brain glucose utilization. In the present study, we hypothesized that increasing n-3 LCPUFA intake at an early age may help to prevent or correct the glucose hypometabolism observed during aging and age-related cognitive decline. The effects of 12 months' supplementation with n-3 LCPUFA on brain glucose utilization assessed by positron emission tomography was tested in young adult mouse lemurs (Microcebus murinus). Cognitive function was tested in parallel in the same animals. Lemurs supplemented with n-3 LCPUFA had higher brain glucose uptake and cerebral metabolic rate of glucose compared with controls in all brain regions. The n-3 LCPUFA-supplemented animals also had higher exploratory activity in an open-field task and lower evidence of anxiety in the Barnes maze. Our results demonstrate for the first time in a nonhuman primate that n-3 LCPUFA supplementation increases brain glucose uptake and metabolism and concomitantly reduces anxiety. Copyright © 2015 by the American Society for Biochemistry and Molecular Biology, Inc.

Intertemporal choice in lemurs.

PubMed

Stevens, Jeffrey R; Mühlhoff, Nelly

2012-02-01

Different species vary in their ability to wait for delayed rewards in intertemporal choice tasks. Models of rate maximization account for part of this variation, but other factors such as social structure and feeding ecology seem to underly some species differences. Though studies have evaluated intertemporal choice in several primate species, including Old World monkeys, New World monkeys, and apes, prosimians have not been tested. This study investigated intertemporal choices in three species of lemur (black-and-white ruffed lemurs, Varecia variegata, red ruffed lemurs, Varecia rubra, and black lemurs, Eulemur macaco) to assess how they compare to other primate species and whether their choices are consistent with rate maximization. We offered lemurs a choice between two food items available immediately and six food items available after a delay. We found that by adjusting the delay to the larger reward, the lemurs were indifferent between the two options at a mean delay of 17 s, ranging from 9 to 25 s. These data are comparable to data collected from common marmosets (Callithrix jacchus). The lemur data were not consistent with models of rate maximization. The addition of lemurs to the list of species tested in these tasks will help uncover the role of life history and socio-ecological factors influencing intertemporal choices. Copyright © 2011 Elsevier B.V. All rights reserved.

Induction of Antioxidant and Heat Shock Protein Responses During Torpor in the Gray Mouse Lemur, Microcebus murinus.

PubMed

Wu, Cheng-Wei; Biggar, Kyle K; Zhang, Jing; Tessier, Shannon N; Pifferi, Fabien; Perret, Martine; Storey, Kenneth B

2015-04-01

A natural tolerance of various environmental stresses is typically supported by various cytoprotective mechanisms that protect macromolecules and promote extended viability. Among these are antioxidant defenses that help to limit damage from reactive oxygen species and chaperones that help to minimize protein misfolding or unfolding under stress conditions. To understand the molecular mechanisms that act to protect cells during primate torpor, the present study characterizes antioxidant and heat shock protein (HSP) responses in various organs of control (aroused) and torpid gray mouse lemurs, Microcebus murinus. Protein expression of HSP70 and HSP90α was elevated to 1.26 and 1.49 fold, respectively, in brown adipose tissue during torpor as compared with control animals, whereas HSP60 in liver of torpid animals was 1.15 fold of that in control (P<0.05). Among antioxidant enzymes, protein levels of thioredoxin 1 were elevated to 2.19 fold in white adipose tissue during torpor, whereas Cu-Zn superoxide dismutase 1 levels rose to 1.1 fold in skeletal muscle (P<0.05). Additionally, total antioxidant capacity was increased to 1.6 fold in liver during torpor (P<0.05), while remaining unchanged in the five other tissues. Overall, our data suggest that antioxidant and HSP responses are modified in a tissue-specific manner during daily torpor in gray mouse lemurs. Furthermore, our data also show that cytoprotective strategies employed during primate torpor are distinct from the strategies in rodent hibernation as reported in previous studies. Copyright © 2015. Production and hosting by Elsevier Ltd.

Lemur Biorhythms and Life History Evolution.

PubMed

Hogg, Russell T; Godfrey, Laurie R; Schwartz, Gary T; Dirks, Wendy; Bromage, Timothy G

2015-01-01

Skeletal histology supports the hypothesis that primate life histories are regulated by a neuroendocrine rhythm, the Havers-Halberg Oscillation (HHO). Interestingly, subfossil lemurs are outliers in HHO scaling relationships that have been discovered for haplorhine primates and other mammals. We present new data to determine whether these species represent the general lemur or strepsirrhine condition and to inform models about neuroendocrine-mediated life history evolution. We gathered the largest sample to date of HHO data from histological sections of primate teeth (including the subfossil lemurs) to assess the relationship of these chronobiological measures with life history-related variables including body mass, brain size, age at first female reproduction, and activity level. For anthropoids, these variables show strong correlations with HHO conforming to predictions, though body mass and endocranial volume are strongly correlated with HHO periodicity in this group. However, lemurs (possibly excepting Daubentonia) do not follow this pattern and show markedly less variability in HHO periodicity and lower correlation coefficients and slopes. Moreover, body mass is uncorrelated, and brain size and activity levels are more strongly correlated with HHO periodicity in these animals. We argue that lemurs evolved this pattern due to selection for risk-averse life histories driven by the unpredictability of the environment in Madagascar. These results reinforce the idea that HHO influences life history evolution differently in response to specific ecological selection regimes.

Lemur Biorhythms and Life History Evolution

PubMed Central

Hogg, Russell T.; Godfrey, Laurie R.; Schwartz, Gary T.; Dirks, Wendy; Bromage, Timothy G.

2015-01-01

Skeletal histology supports the hypothesis that primate life histories are regulated by a neuroendocrine rhythm, the Havers-Halberg Oscillation (HHO). Interestingly, subfossil lemurs are outliers in HHO scaling relationships that have been discovered for haplorhine primates and other mammals. We present new data to determine whether these species represent the general lemur or strepsirrhine condition and to inform models about neuroendocrine-mediated life history evolution. We gathered the largest sample to date of HHO data from histological sections of primate teeth (including the subfossil lemurs) to assess the relationship of these chronobiological measures with life history-related variables including body mass, brain size, age at first female reproduction, and activity level. For anthropoids, these variables show strong correlations with HHO conforming to predictions, though body mass and endocranial volume are strongly correlated with HHO periodicity in this group. However, lemurs (possibly excepting Daubentonia) do not follow this pattern and show markedly less variability in HHO periodicity and lower correlation coefficients and slopes. Moreover, body mass is uncorrelated, and brain size and activity levels are more strongly correlated with HHO periodicity in these animals. We argue that lemurs evolved this pattern due to selection for risk-averse life histories driven by the unpredictability of the environment in Madagascar. These results reinforce the idea that HHO influences life history evolution differently in response to specific ecological selection regimes. PMID:26267241

Object permanence in lemurs.

PubMed

Deppe, Anja M; Wright, Patricia C; Szelistowski, William A

2009-03-01

Object permanence, the ability to mentally represent objects that have disappeared from view, should be advantageous to animals in their interaction with the natural world. The objective of this study was to examine whether lemurs possess object permanence. Thirteen adult subjects representing four species of diurnal lemur (Eulemur fulvus rufus, Eulemur mongoz, Lemur catta and Hapalemur griseus) were presented with seven standard Piagetian visible and invisible object displacement tests, plus one single visible test where the subject had to wait predetermined times before allowed to search, and two invisible tests where each hiding place was made visually unique. In all visible tests lemurs were able to find an object that had been in clear view before being hidden. However, when lemurs were not allowed to search for up to 25-s, performance declined with increasing time-delay. Subjects did not outperform chance on any invisible displacements regardless of whether hiding places were visually uniform or unique, therefore the upper limit of object permanence observed was Stage 5b. Lemur species in this study eat stationary foods and are not subject to stalking predators, thus Stage 5 object permanence is probably sufficient to solve most problems encountered in the wild.

Quantitative assessment of testicular germ cell production and kinematic and morphometric parameters of ejaculated spermatozoa in the grey mouse lemur, Microcebus murinus.

PubMed

Aslam, H; Schneiders, A; Perret, M; Weinbauer, G F; Hodges, J K

2002-02-01

Germ cell production and organization of the testicular epithelium in a prosimian species, the grey mouse lemur, Microcebus murinus, was investigated to extend knowledge of comparative primate spermatogenesis. In addition, semen samples collected from adult male lemurs (body weight 53-92 g; n = 16) by rectal probe electroejaculation were evaluated using computer-assisted morphometric and kinematic analysis of spermatozoa. Epididymidal spermatozoa were collected from six animals after hemicastration; the testes were weighed and prepared for stereological analysis and flow cytometry. The relative testis mass (as a percentage of body weight) ranged between 1.17 and 5.6%. Twelve stages of testicular seminiferous epithelium as described for macaques were applied and only a single stage was observed in most of the seminiferous tubule cross-sections. On average (mean SD), a single testis contained 1870 +/- 829 x 10(6) germ cells and 35 +/- 12 x 10(6) Sertoli cells. Germ cell ratios (preleptotene:type B spermatogonia = 2, round spermatid:pachytene = 3; elongated spermatid:round spermatids = 1) indicated high spermatogenic efficacy. Sperm head dimensions and tail lengths of the ejaculated and epididymidal spermatozoa were similar. Percentages of defects (neck/mid-piece and tail) were low ( 10%) and similar for ejaculated and epididymidal spermatozoa. Spermatozoa were highly motile, characterized by extensive lateral head displacement, but relatively low progressive motility. In conclusion, the grey mouse lemur has unusually large testes with a highly efficient spermatogenic process and large sperm output. These features, together with the high proportion of morphologically normal and highly motile spermatozoa in the ejaculates, indicate that Microcebus murinus is a species in which sperm competition after ejaculation is likely to occur. The predominantly single spermatogenic stage system seems to be an ancestral feature among primates.

An Alu-Based Phylogeny of Lemurs (Infraorder: Lemuriformes)

PubMed Central

McLain, Adam T.; Meyer, Thomas J.; Faulk, Christopher; Herke, Scott W.; Oldenburg, J. Michael; Bourgeois, Matthew G.; Abshire, Camille F.

2012-01-01

Lemurs (infraorder: Lemuriformes) are a radiation of strepsirrhine primates endemic to the island of Madagascar. As of 2012, 101 lemur species, divided among five families, have been described. Genetic and morphological evidence indicates all species are descended from a common ancestor that arrived in Madagascar ∼55–60 million years ago (mya). Phylogenetic relationships in this species-rich infraorder have been the subject of debate. Here we use Alu elements, a family of primate-specific Short INterspersed Elements (SINEs), to construct a phylogeny of infraorder Lemuriformes. Alu elements are particularly useful SINEs for the purpose of phylogeny reconstruction because they are identical by descent and confounding events between loci are easily resolved by sequencing. The genome of the grey mouse lemur (Microcebus murinus) was computationally assayed for synapomorphic Alu elements. Those that were identified as Lemuriformes-specific were analyzed against other available primate genomes for orthologous sequence in which to design primers for PCR (polymerase chain reaction) verification. A primate phylogenetic panel of 24 species, including 22 lemur species from all five families, was examined for the presence/absence of 138 Alu elements via PCR to establish relationships among species. Of these, 111 were phylogenetically informative. A phylogenetic tree was generated based on the results of this analysis. We demonstrate strong support for the monophyly of Lemuriformes to the exclusion of other primates, with Daubentoniidae, the aye-aye, as the basal lineage within the infraorder. Our results also suggest Lepilemuridae as a sister lineage to Cheirogaleidae, and Indriidae as sister to Lemuridae. Among the Cheirogaleidae, we show strong support for Microcebus and Mirza as sister genera, with Cheirogaleus the sister lineage to both. Our results also support the monophyly of the Lemuridae. Within Lemuridae we place Lemur and Hapalemur together to the exclusion of

Adult play fighting and potential role of tail signals in ringtailed lemurs (Lemur catta).

PubMed

Palagi, Elisabetta

2009-02-01

Adult strepsirrhines have been completely neglected in the study of animal play. I focused on adult play fighting and the role of tail-play as a signal in ringtailed lemurs (Lemur catta). Tail-play is performed during play fighting, when lemurs anoint or, more rarely, wave their tails toward the playmate. During the prereproductive period, male and female lemurs engaged in play fighting with comparable frequencies, as was expected to occur in monomorphic species such as L. catta. The dyads showing low aggression rates engaged most frequently in play fighting, and polyadic play was frequently performed. Signals seem to be important in avoiding escalation to real aggression, especially when the playfulness of performers can be misunderstood by recipients. Tail-play was most frequent (a) in the dyads with low grooming rates (low familiarity degree) and (b) during the most risky play sessions (polyadic ones). Thus, tail-play can be considered as a useful tool for play communication in ringtailed lemurs. Copyright 2009 APA, all rights reserved.

The Lemur Conjecture

NASA Astrophysics Data System (ADS)

Lanzagorta, Marco; Jitrik, Oliverio; Uhlmann, Jeffrey; Venegas-Andraca, Salvador E.

2017-05-01

In previous research we designed an interferometric quantum seismograph that uses entangled photon states to enhance sensitivity in an optomechanic device. However, a spatially-distributed array of such sensors, with each sensor measuring only nm-vibrations, may not provide sufficient sensitivity for the prediction of major earthquakes because it fails to exploit potentially critical phase information. We conjecture that relative phase information can explain the anecdotal observations that animals such as lemurs exhibit sensitivity to impending earthquakes earlier than can be done confidently with traditional seismic technology. More specifically, we propose that lemurs use their limbs as ground motion sensors and that relative phase differences are fused in the brain in a manner similar to a phased-array or synthetic-aperture radar. In this paper we will describe a lemur-inspired quantum sensor network for early warning of earthquakes. The system uses 4 interferometric quantum seismographs (e.g., analogous to a lemurs limbs) and then conducts phase and data fusion of the seismic information. Although we discuss a quantum-based technology, the principles described can also be applied to classical sensor arrays

Captive Conditions of Pet Lemurs in Madagascar.

PubMed

Reuter, Kim E; Schaefer, Melissa S

2016-01-01

Live extraction of wildlife is a threat to biodiversity and can compromise animal welfare standards. Studies of the captive environments and welfare of pet primates are known, but none has focused on Madagascar. We aimed to expand knowledge about the captive conditions of pet lemurs in Madagascar. We hypothesized that captive lemurs would often be kept in restrictive settings, including small cages, would be fed foods inconsistent with their natural diets and, as a result, would be in bad physical or psychological health. Data were collected via a web-based survey (n = 253 reports) and from the websites and social media pages of 25 hotels. Most lemurs seen by respondents were either kept on a rope/leash/chain or in a cage (67%), though some lemurs were habituated and were not restrained (28%). Most of the time (72%) cages were considered small, and lemurs were rarely kept in captivity together with other lemurs (81% of lemurs were caged alone). Pet lemurs were often fed foods inconsistent with their natural diets, and most (53%) were described as being in bad health. These findings point to a need to undertake outreach to pet lemur owners in Madagascar about the captivity requirements of primates. © 2016 S. Karger AG, Basel.

Coat condition of ringtailed lemurs, Lemur catta at Berenty Reserve, Madagascar: I. Differences by age, sex, density and tourism, 1996-2006.

PubMed

Jolly, Alison

2009-03-01

An index of coat condition can be a non-invasive tool for tracking health and stress at population level. Coat condition in ringtailed lemurs, Lemur catta, was recorded during September-November birth seasons of 1996, 1997, 1999, and 2001-2006 at Berenty Reserve, Madagascar. Condition was scored on a scale from 0: full, fluffy coat with guard hairs present, to 5: half or more of body hairless. Adult males did not differ overall from adult females. Coats were worse in adults than in 2-year-old subadults; 1-year-old juveniles were intermediate. Mothers and adult males lost coat condition as the season progressed: non-mother females maintained condition. Years 1999-2002 scored better coats than either 1996-1997 or 2003-2006. Lemurs in high population density areas had worse coats than in natural forest, but tourist presence had less effect than density. Monitoring coat condition in an apparently healthy population reveals differences between population segments, and in a forest fragment with limited immigration or emigration it can track progressive changes, correcting impressions of progressive improvement or degradation over time. Above all it gives a baseline for response to climate changes or eventual pathology. (c) 2008 Wiley-Liss, Inc.

Species-Specific Transmission of Novel Picornaviruses in Lemurs

PubMed Central

Lim, Efrem S.; Deem, Sharon L.; Porton, Ingrid J.; Cao, Song

2015-01-01

ABSTRACT The roles of host genetics versus exposure and contact frequency in driving cross-species transmission remain the subject of debate. Here, we used a multitaxon lemur collection at the Saint Louis Zoo in the United States as a model to gain insight into viral transmission in a setting of high interspecies contact. Lemurs are a diverse and understudied group of primates that are highly endangered. The speciation of lemurs, which are endemic to the island of Madagascar, occurred in geographic isolation apart from that of continental African primates. Although evidence of endogenized viruses in lemur genomes exists, no exogenous viruses of lemurs have been described to date. Here we identified two novel picornaviruses in fecal specimens of ring-tailed lemurs (Lemur catta) and black-and-white ruffed lemurs (Varecia variegata). We found that the viruses were transmitted in a species-specific manner (lesavirus 1 was detected only in ring-tailed lemurs, while lesavirus 2 was detected only in black-and-white ruffed lemurs). Longitudinal sampling over a 1-year interval demonstrated ongoing infection in the collection. This was supported by evidence of viral clearance in some animals and new infections in previously uninfected animals, including a set of newly born triplets that acquired the infection. While the two virus strains were found to be cocirculating in a mixed-species exhibit of ring-tailed lemurs, black-and-white ruffed lemurs, and black lemurs, there was no evidence of cross-species transmission. This suggests that despite high-intensity contact, host species barriers can prevent cross-species transmissions of these viruses. IMPORTANCE Up to 75% of emerging infectious diseases in humans today are the result of zoonotic transmission. However, a challenge in understanding transmission dynamics has been the limited models of cross-species transmission. Zoos provide a unique opportunity to explore parameters defining viral transmission. We demonstrated that

RADIOGRAPHIC AND ULTRASONOGRAPHIC ABDOMINAL ANATOMY IN CAPTIVE RING-TAILED LEMURS (LEMUR CATTA).

PubMed

Makungu, Modesta; du Plessis, Wencke M; Barrows, Michelle; Groenewald, Hermanus B; Koeppel, Katja N

2016-06-01

The ring-tailed lemur (Lemur catta) is primarily distributed in south and southwestern Madagascar. It is classified as an endangered species by the International Union for Conservation of Nature. Various abdominal diseases, such as hepatic lipidosis, intestinal ulcers, cystitis, urinary tract obstruction, and neoplasia (e.g., colonic adenocarcinoma and cholangiocarcinoma), have been reported in this species. The aim of this study was to describe the normal radiographic and ultrasonographic abdominal anatomy in captive ring-tailed lemurs to provide guidance for clinical use. Radiography of the abdomen and ultrasonography of the liver, spleen, kidneys, and urinary bladder were performed in 13 and 9 healthy captive ring-tailed lemurs, respectively, during their annual health examinations. Normal radiographic and ultrasonographic reference ranges for abdominal organs were established and ratios were calculated. The majority (12/13) of animals had seven lumbar vertebrae. The sacrum had mainly (12/13) three segments. Abdominal serosal detail was excellent in all animals, and hypaxial muscles were conspicuous in the majority (11/13) of animals. The spleen was frequently (12/13) seen on the ventrodorsal (VD) view and rarely (3/13) on the right lateral (RL) view. The liver was less prominent and well contained within the ribcage. The pylorus was mostly (11/13) located to the right of the midline. The right and left kidneys were visible on the RL and VD views, with the right kidney positioned more cranial and dorsal to the left kidney. On ultrasonography, the kidneys appeared ovoid on transverse and longitudinal views. The medulla was hypoechoic to the renal cortex. The renal cortex was frequently (8/9) isoechoic and rarely (1/9) hyperechoic to the splenic parenchyma. The liver parenchyma was hypoechoic (5/5) to the renal cortex. Knowledge of the normal radiographic and ultrasonographic abdominal anatomy of ring-tailed lemurs may be useful in the diagnosis of diseases and in

A comparison of salivary pH in sympatric wild lemurs (Lemur catta and Propithecus verreauxi) at Beza Mahafaly Special Reserve, Madagascar.

PubMed

Cuozzo, Frank P; Sauther, Michelle L; Yamashita, Nayuta; Lawler, Richard R; Brockman, Diane K; Godfrey, Laurie R; Gould, Lisa; Youssouf, Ibrahim Antho Jacky; Lent, Cheryl; Ratsirarson, Joelisoa; Richard, Alison F; Scott, Jessica R; Sussman, Robert W; Villers, Lynne M; Weber, Martha A; Willis, George

2008-04-01

Chemical deterioration of teeth is common among modern humans, and has been suggested for some extinct primates. Dental erosion caused by acidic foods may also obscure microwear signals of mechanical food properties. Ring-tailed lemurs at the Beza Mahafaly Special Reserve (BMSR), Madagascar, display frequent severe tooth wear and subsequent tooth loss. In contrast, sympatric Verreaux's sifaka display far less tooth wear and infrequent tooth loss, despite both species regularly consuming acidic tamarind fruit. We investigated the potential impact of dietary acidity on tooth wear, collecting data on salivary pH from both species, as well as salivary pH from ring-tailed lemurs at Tsimanampesotse National Park, Madagascar. We also collected salivary pH data from ring-tailed lemurs at the Indianapolis Zoo, none of which had eaten for at least 12 hr before data collection. Mean salivary pH for the BMSR ring-tailed lemurs (8.098, n=41, SD=0.550) was significantly more alkaline than Verreaux's sifaka (7.481, n=26, SD=0.458). The mean salivary pH of BMSR (8.098) and Tsimanampesotse (8.080, n=25, SD=0.746) ring-tailed lemurs did not differ significantly. Salivary pH for the Indianapolis Zoo sample (8.125, n=16, SD=0.289) did not differ significantly from either the BMSR or Tsimanampesotse ring-tailed lemurs, but was significantly more alkaline than the BMSR Verreaux's sifaka sample. Regardless of the time between feeding and collection of pH data (from several minutes to nearly 1 hr), salivary pH for each wild lemur was above the "critical" pH of 5.5, below which enamel demineralization occurs. Thus, the high pH of lemur saliva suggests a strong buffering capacity, indicating the impact of acidic foods on dental wear is short-lived, likely having a limited effect. However, tannins in tamarind fruit may increase friction between teeth, thereby increasing attrition and wear in lemurs. These data also suggest that salivary pH varies between lemur species, corresponding to broad

Coevolution of Cyanogenic Bamboos and Bamboo Lemurs on Madagascar

PubMed Central

Ballhorn, Daniel J.; Rakotoarivelo, Fanny Patrika; Kautz, Stefanie

2016-01-01

Feeding strategies of specialist herbivores often originate from the coevolutionary arms race of plant defenses and counter-adaptations of herbivores. The interaction between bamboo lemurs and cyanogenic bamboos on Madagascar represents a unique system to study diffuse coevolutionary processes between mammalian herbivores and plant defenses. Bamboo lemurs have different degrees of dietary specialization while bamboos show different levels of chemical defense. In this study, we found variation in cyanogenic potential (HCNp) and nutritive characteristics among five sympatric bamboo species in the Ranomafana area, southeastern Madagascar. The HCNp ranged from 209±72 μmol cyanide*g-1 dwt in Cathariostachys madagascariensis to no cyanide in Bambusa madagascariensis. Among three sympatric bamboo lemur species, the greater bamboo lemur (Prolemur simus) has the narrowest food range as it almost exclusively feeds on the highly cyanogenic C. madagascariensis. Our data suggest that high HCNp is the derived state in bamboos. The ancestral state of lemurs is most likely "generalist" while the ancestral state of bamboo lemurs was determined as equivocal. Nevertheless, as recent bamboo lemurs comprise several "facultative specialists" and only one "obligate specialist" adaptive radiation due to increased flexibility is likely. We propose that escaping a strict food plant specialization enabled facultative specialist bamboo lemurs to inhabit diverse geographical areas. PMID:27532127

Impaired fasting blood glucose is associated to cognitive impairment and cerebral atrophy in middle-aged non-human primates

PubMed Central

Djelti, Fathia; Dhenain, Marc; Terrien, Jérémy; Picq, Jean-Luc; Hardy, Isabelle; Champeval, Delphine; Perret, Martine; Schenker, Esther; Epelbaum, Jacques; Aujard, Fabienne

2017-01-01

Age-associated cognitive impairment is a major health and social issue because of increasing aged population. Cognitive decline is not homogeneous in humans and the determinants leading to differences between subjects are not fully understood. In middle-aged healthy humans, fasting blood glucose levels in the upper normal range are associated with memory impairment and cerebral atrophy. Due to a close evolutional similarity to Man, non-human primates may be useful to investigate the relationships between glucose homeostasis, cognitive deficits and structural brain alterations. In the grey mouse lemur, Microcebus murinus, spatial memory deficits have been associated with age and cerebral atrophy but the origin of these alterations have not been clearly identified. Herein, we showed that, on 28 female grey mouse lemurs (age range 2.4-6.1 years-old), age correlated with impaired fasting blood glucose (rs=0.37) but not with impaired glucose tolerance or insulin resistance. In middle-aged animals (4.1-6.1 years-old), fasting blood glucose was inversely and closely linked with spatial memory performance (rs=0.56) and hippocampus (rs=−0.62) or septum (rs=−0.55) volumes. These findings corroborate observations in humans and further support the grey mouse lemur as a natural model to unravel mechanisms which link impaired glucose homeostasis, brain atrophy and cognitive processes. PMID:28039490

Impaired fasting blood glucose is associated to cognitive impairment and cerebral atrophy in middle-aged non-human primates.

PubMed

Djelti, Fathia; Dhenain, Marc; Terrien, Jérémy; Picq, Jean-Luc; Hardy, Isabelle; Champeval, Delphine; Perret, Martine; Schenker, Esther; Epelbaum, Jacques; Aujard, Fabienne

2016-12-28

Age-associated cognitive impairment is a major health and social issue because of increasing aged population. Cognitive decline is not homogeneous in humans and the determinants leading to differences between subjects are not fully understood. In middle-aged healthy humans, fasting blood glucose levels in the upper normal range are associated with memory impairment and cerebral atrophy. Due to a close evolutional similarity to Man, non-human primates may be useful to investigate the relationships between glucose homeostasis, cognitive deficits and structural brain alterations. In the grey mouse lemur, Microcebus murinus , spatial memory deficits have been associated with age and cerebral atrophy but the origin of these alterations have not been clearly identified. Herein, we showed that, on 28 female grey mouse lemurs (age range 2.4-6.1 years-old), age correlated with impaired fasting blood glucose (r s =0.37) but not with impaired glucose tolerance or insulin resistance. In middle-aged animals (4.1-6.1 years-old), fasting blood glucose was inversely and closely linked with spatial memory performance (r s =0.56) and hippocampus (r s =-0.62) or septum (r s =-0.55) volumes. These findings corroborate observations in humans and further support the grey mouse lemur as a natural model to unravel mechanisms which link impaired glucose homeostasis, brain atrophy and cognitive processes.

Testing the adaptive radiation hypothesis for the lemurs of Madagascar.

PubMed

Herrera, James P

2017-01-01

Lemurs, the diverse, endemic primates of Madagascar, are thought to represent a classic example of adaptive radiation. Based on the most complete phylogeny of living and extinct lemurs yet assembled, I tested predictions of adaptive radiation theory by estimating rates of speciation, extinction and adaptive phenotypic evolution. As predicted, lemur speciation rate exceeded that of their sister clade by nearly twofold, indicating the diversification dynamics of lemurs and mainland relatives may have been decoupled. Lemur diversification rates did not decline over time, however, as predicted by adaptive radiation theory. Optimal body masses diverged among dietary and activity pattern niches as lineages diversified into unique multidimensional ecospace. Based on these results, lemurs only partially fulfil the predictions of adaptive radiation theory, with phenotypic evolution corresponding to an 'early burst' of adaptive differentiation. The results must be interpreted with caution, however, because over the long evolutionary history of lemurs (approx. 50 million years), the 'early burst' signal of adaptive radiation may have been eroded by extinction.

The effects of environmental and visitor variables on the behavior of free-ranging ring-tailed lemurs (Lemur catta) in captivity.

PubMed

Collins, Courtney; Corkery, Ilse; Haigh, Amy; McKeown, Sean; Quirke, Thomas; O'Riordan, Ruth

2017-07-01

The effect of the zoo environment on captive animals is an increasingly studied area of zoo research, with visitor effects and exhibit design recognized as two of the factors that can contribute to animal welfare in captivity. It is known that in some situations, visitors may be stressful to zoo-housed primates, and this may be compounded by environmental factors such as the weather, the time of day, and zoo husbandry routines. Exhibit design and proximity of the public are also known to influence behavioral response of primates to visitors; however, there is minimal research on free-ranging zoo animals, even though they are potentially subjected to intense interactions with visitors. The current study explores the effect of the zoo environment, several visitor variables and specific animal-visitor interactions on the behavior of free-ranging ring-tailed lemurs (Lemur catta) at Fota Wildlife Park, Ireland. Data were obtained through scan samples collected over 18 months (n = 12,263) and analyzed using a range of statistical tests, including general estimating equations (GEE). Results demonstrate that the free-ranging lemurs' behavior at Fota Wildlife Park is affected by season, weather and time of day. Similarities in feeding behavior exist between the free-ranging group and lemurs in the wild when resources are plentiful. Visitor variables had a limited effect on lemur behavior and behavioral diversity level. Lemurs rarely reacted to visitors when specific interactions were considered. Generally, the results indicate that the ring-tailed lemurs in this study have adapted well to the zoo environment and habituated to visitors. © 2017 Wiley Periodicals, Inc.

Testing the adaptive radiation hypothesis for the lemurs of Madagascar

PubMed Central

2017-01-01

Lemurs, the diverse, endemic primates of Madagascar, are thought to represent a classic example of adaptive radiation. Based on the most complete phylogeny of living and extinct lemurs yet assembled, I tested predictions of adaptive radiation theory by estimating rates of speciation, extinction and adaptive phenotypic evolution. As predicted, lemur speciation rate exceeded that of their sister clade by nearly twofold, indicating the diversification dynamics of lemurs and mainland relatives may have been decoupled. Lemur diversification rates did not decline over time, however, as predicted by adaptive radiation theory. Optimal body masses diverged among dietary and activity pattern niches as lineages diversified into unique multidimensional ecospace. Based on these results, lemurs only partially fulfil the predictions of adaptive radiation theory, with phenotypic evolution corresponding to an ‘early burst’ of adaptive differentiation. The results must be interpreted with caution, however, because over the long evolutionary history of lemurs (approx. 50 million years), the ‘early burst’ signal of adaptive radiation may have been eroded by extinction. PMID:28280597

Social organization of the Alaotran gentle lemur (Hapalemur griseus alaotrensis).

PubMed

Mutschler, T; Nievergelt, C M; Feistner, A T

2000-01-01

Knowledge of the social organization of lemurs is still limited for most species. Where there is sufficient information, it has been shown that lemur social organization differs in essential points from that of other primates. In the field study reported here, demographic structure and life-history processes were investigated in order to characterize the social organization of the Alaotran gentle lemur (Hapalemur griseus alaotrensis). Data were obtained through captures and observations. Alaotran gentle lemurs were found in small groups of up to nine individuals. Although most groups contained just one breeding female, a substantial proportion of groups (35%) had two breeding females. Therefore, Alaotran gentle lemurs cannot be classed as being organized in monogamous family groups. An extended birth season was found, and groups with two breeding females had significantly higher breeding output per adult than groups with a single adult female. Limited data suggest that females emigrate from their natal group while still subadult, whereas males can stay in the natal group until they are fully grown and disperse as adults. Variability in group composition, significantly higher reproductive output per adult in groups with two breeding females, and delayed dispersal of males suggest that Alaotran gentle lemurs pursue a resource-defense mating strategy, rather than a female-defense mating strategy. The suggestion that extant social lemurs may have evolved from a monogamous system, could explain the differences between lemur social systems and those of other primates.

Lemur traits and Madagascar ecology: coping with an island environment.

PubMed

Wright, P C

1999-01-01

The last decade's lemur research includes successes in discovering new living and extinct species and learning about the distribution, biogeography, physiology, behavior, and ecology of previously little-studied species. In addition, in both the dry forest and rain forest, long-term studies of lemur demography, life history, and reproduction, have been completed in conjunction with data on tree productivity, phenology, and climate. Lemurs contrast with anthropoids in several behavioral features, including female dominance, targeted female-female aggression, lack of sexual dimorphism regardless of mating system, sperm competition coupled with male-male aggression, high infant mortality, cathemerality, and strict seasonal breeding. Hypotheses to explain these traits include the "energy conservation hypothesis" (ECH) suggesting that harsh and unpredictable climate factors on the island of Madagascar have affected the evolution of female dominance, and the "evolutionary disequilibrium hypotheses" (EVDH) suggesting that the recent megafauna extinctions have influenced lemurs to become diurnal. These hypotheses are compared and contrasted in light of recent empirical data on climate, subfossils, and lemur behavior. New data on life histories of the rain forest lemurs at Ranomafana National Park give further support to the ECH. Birth seasons are synchronized within each species, but there is a 6-month distribution of births among species. Gestation and lactation lengths vary among sympatric lemurs, but all lemur species in the rain forest wean in synchrony at the season most likely to have abundant resources. Across-species weaning synchrony seen in Ranomafana corroborates data from the dry forest that late lactation and weaning is the life history event that is the primary focus of the annual schedule. Lemur adaptations may assure maximum offspring survival in this environment with an unpredictable food supply and heavy predation. In conclusion, a more comprehensive

Pair-bonding, female aggression and the evolution of lemur societies.

PubMed

Jolly, A

1998-01-01

Lemur societies have been described as convergent with those of anthropoids, including Papio-like female-bonded multi-male groups. Recent research, however, shows at least 5 pair-bonded species among the Lemuridae and Indriidae. Three more, Eulemur mongoz, Eulemur fulvus and Varecia variegata, have societies combining aspects of pairing with aspects of troop life. The best-known female-bonded societies, those of Lemur catta, Propithecus diadema edwardsi and Propithecus verreauxi, may be assemblages of mother-daughter dyads, capable of high aggression towards other females, but derived from more solitary female ancestors, perhaps also living as pairs. The internal structure of such lemur groups differs from the more extensive kin groups of catarrhines. This in turn may relate to the lemurs' level of social intelligence and to lemur female dominance over males.

Lemur species-specific metapopulation responses to habitat loss and fragmentation

PubMed Central

Lehman, Shawn M.

2018-01-01

Determining what factors affect species occurrence is vital to the study of primate biogeography. We investigated the metapopulation dynamics of a lemur community consisting of eight species (Avahi occidentalis, Propithecus coquereli, Microcebus murinus, Microcebus ravelobensis, Lepilemur edwardsi, Cheirogaleus medius, Eulemur mongoz, and Eulemur fulvus) within fragmented tropical dry deciduous forest habitat in Ankarafantsika National Park, Madagascar. We measured fragment size and isolation of 42 fragments of forest ranging in size from 0.23 to 117.7 ha adjacent to continuous forest. Between June and November 2011, we conducted 1218 surveys and observed six of eight lemur species (M. murinus, M. ravelobensis, C. medius, E. fulvus, P. coquereli, and L. edwardsi) in the 42 fragments. We applied among patch incidence function models (IFMs) with various measures of dispersal and a mainland-island IFM to lemur species occurrence, with the aim of answering the following questions: 1) Do lemur species in dry deciduous forest fragments form metapopulations? 2) What are the separate effects of area (extinction risk) and connectivity/isolation (colonization potential) within a lemur metapopulation? 3) Within simulated metapopulations over time, how do area and connectivity/isolation affect occurrence? and 4) What are the conservation implications of our findings? We found that M. murinus formed either a mainland-island or an among patch metapopulation, M. ravelobensis formed a mainland-island metapopulation, C. medius and E. fulvus formed among patch metapopulations, and neither P. coquereli or L. edwardsi formed a metapopulation. Metapopulation dynamics and simulations suggest that area was a more consistent positive factor determining lemur species occurrence than fragment isolation and is crucial to the maintenance of lemur populations within this fragmented landscape. Using a metapopulation approach to lemur biogeography is critical for understanding how lemur species

Genetic analysis of hybridization and introgression between wild mongoose and brown lemurs.

PubMed

Pastorini, Jennifer; Zaramody, Alphonse; Curtis, Deborah J; Nievergelt, Caroline M; Mundy, Nicholas I

2009-02-05

Hybrid zones generally represent areas of secondary contact after speciation. The nature of the interaction between genes of individuals in a hybrid zone is of interest in the study of evolutionary processes. In this study, data from nuclear microsatellites and mitochondrial DNA sequences were used to genetically characterize hybridization between wild mongoose lemurs (Eulemur mongoz) and brown lemurs (E. fulvus) at Anjamena in west Madagascar. Two segments of mtDNA have been sequenced and 12 microsatellite loci screened in 162 brown lemurs and mongoose lemurs. Among the mongoose lemur population at Anjamena, we identified two F1 hybrids (one also having the mtDNA haplotype of E. fulvus) and six other individuals with putative introgressed alleles in their genotype. Principal component analysis groups both hybrids as intermediate between E. mongoz and E. fulvus and admixture analyses revealed an admixed genotype for both animals. Paternity testing proved one F1 hybrid to be fertile. Of the eight brown lemurs genotyped, all have either putative introgressed microsatellite alleles and/or the mtDNA haplotype of E. mongoz. Introgression is bidirectional for the two species, with an indication that it is more frequent in brown lemurs than in mongoose lemurs. We conclude that this hybridization occurs because mongoose lemurs have expanded their range relatively recently. Introgressive hybridization may play an important role in the unique lemur radiation, as has already been shown in other rapidly evolving animals.

Behavioral responses of three lemur species to different food enrichment devices.

PubMed

Shapiro, Morgan E; Shapiro, Hannah G; Ehmke, Erin E

2018-05-01

Environmental enrichment is a tool used to promote the welfare and well-being of captive animals by encouraging the display of species-specific behaviors and reducing the stress or boredom induced by captive environments. Lemurs are highly endangered, yet few studies have analyzed the behavioral impacts of enrichment on captive populations. We studied the impacts of two novel enrichment devices on three lemur species (ring-tailed lemurs [Lemur catta], red-ruffed lemurs [Varecia rubra], and Coquerel's sifaka [Propithecus coquereli]) to determine both the overall and species-specific impacts of enrichment on lemur behavior. We recorded lemur behavior using the continuous sampling method to obtain behavior duration and analyzed our results using ANOVA Repeated Measures. Results showed enrichment effectiveness differed for each species and that different enrichment devices had varying impacts on lemur behavior across all species. We attributed the differences in species-specific responses to the unique locomotor patterns and methods of diet acquisition of each species, and the variances in behavioral responses across all species to the characteristics of each device. Our study highlights the importance of species-specific enrichment and encourages further research in this field in order to maximize the positive effects of enrichment, which in turn has the potential to affect the overall well-being of captive populations. © 2018 Wiley Periodicals, Inc.

Evidence for social learning in wild lemurs (Lemur catta).

PubMed

Kendal, Rachel L; Custance, Deborah M; Kendal, Jeremy R; Vale, Gillian; Stoinski, Tara S; Rakotomalala, Nirina Lalaina; Rasamimanana, Hantanirina

2010-08-01

Interest in social learning has been fueled by claims of culture in wild animals. These remain controversial because alternative explanations to social learning, such as asocial learning or ecological differences, remain difficult to refute. Compared with laboratory-based research, the study of social learning in natural contexts is in its infancy. Here, for the first time, we apply two new statistical methods, option-bias analysis and network-based diffusion analysis, to data from the wild, complemented by standard inferential statistics. Contrary to common thought regarding the cognitive abilities of prosimian primates, our evidence is consistent with social learning within subgroups in the ring-tailed lemur (Lemur catta), supporting the theory of directed social learning (Coussi-Korbel & Fragaszy, 1995). We also caution that, as the toolbox for capturing social learning in natural contexts grows, care is required in ensuring that the methods employed are appropriate-in particular, regarding social dynamics among study subjects. Supplemental materials for this article may be downloaded from http://lb.psychonomic-journals.org/content/supplemental.

Does habitat disturbance affect stress, body condition and parasitism in two sympatric lemurs?

PubMed Central

Rakotoniaina, Josué H; Kappeler, Peter M; Ravoniarimbinina, Pascaline; Pechouskova, Eva; Hämäläinen, Anni M; Grass, Juliane; Kirschbaum, Clemens; Kraus, Cornelia

2016-01-01

Abstract Understanding how animals react to human-induced changes in their environment is a key question in conservation biology. Owing to their potential correlation with fitness, several physiological parameters are commonly used to assess the effect of habitat disturbance on animals’ general health status. Here, we studied how two lemur species, the fat-tailed dwarf lemur (Cheirogaleus medius) and the grey mouse lemur (Microcebus murinus), respond to changing environmental conditions by comparing their stress levels (measured as hair cortisol concentration), parasitism and general body condition across four habitats ordered along a gradient of human disturbance at Kirindy Forest, Western Madagascar. These two species previously revealed contrasting responses to human disturbance; whereas M. murinus is known as a resilient species, C. medius is rarely encountered in highly disturbed habitats. However, neither hair cortisol concentrations nor parasitism patterns (prevalence, parasite species richness and rate of multiple infections) and body condition varied across the gradient of anthropogenic disturbance. Our results indicate that the effect of anthropogenic activities at Kirindy Forest is not reflected in the general health status of both species, which may have developed a range of behavioural adaptations to deal with suboptimal conditions. Nonetheless, a difference in relative density among sites suggests that the carrying capacity of disturbed habitat is lower, and both species respond differently to environmental changes, with C. medius being more negatively affected. Thus, even for behaviourally flexible species, extended habitat deterioration could hamper long-term viability of populations. PMID:27656285

Unusual sleeping site selection by southern bamboo lemurs.

PubMed

Eppley, Timothy M; Donati, Giuseppe; Ganzhorn, Jörg U

2016-04-01

Selection of sleeping sites has consequences for individual fitness. Non-human primates often bias their selection towards arboreal sites, and the lemurs of Madagascar typically rest/sleep in trees, tree holes, and/or constructed nests. Three non-mutually exclusive hypotheses to explain sleeping site selection include protection from predators, avoidance of parasitic vectors, and improved thermoregulation. Here, we examine these hypotheses for the unusual sleeping site selections by the southern bamboo lemur (Hapalemur meridionalis). Within the Mandena littoral forest of southeast Madagascar, the southern bamboo lemur is known for its ecological flexibility compared to other bamboo lemur species, including a dietary niche expansion to feeding on the ground. Between October 2012 and December 2013, we observed bamboo lemurs from three social groups for 1778.67 h, conducting full-day focal follows on 11 adult individuals (five males, six females). During this period, all three groups were observed to sleep on the ground, with one of these groups also using an abandoned nest of a Madagascar crested ibis (Lophotibis cristata). We collected habitat and temperature data to examine whether selection was influenced by environmental variables. Terrestrial sleeping (N = 17) was observed in all individuals but one adult female, with individuals burrowing under thick vegetation more often during the hot austral summer. While difficult to rigorously test, it is possible that terrestrial sleep sites and/or sleeping in a bird nest may impair visual detection by some aerial and terrestrial predators. Neither of these sites (i.e., terrestrial sleeping or use of a bird nest), however, is likely to minimize exposure to parasites/vectors. Terrestrial sleeping appears to support a thermoregulatory strategy, whereas the use of a bird nest could not be empirically tested. Our observations of unique sleeping site locations used by southern bamboo lemurs further the complexity of their

Sex ratios provide evidence for monozygotic twinning in the ring-tailed lemur, Lemur catta.

PubMed

St Clair, John; Campbell-Palmer, Roisin; Lathe, Richard

2014-02-01

Monozygotic (MZ) twinning is generally considered to be rare in species other than human. We inspected sex ratios in European zoo-bred ring-tailed lemurs (Lemur catta), revealing a significant excess of same-sex twins. Of 94 pairs, 60 (64%) were either both males or both females (p = .004). Application of the Weinberg differential rule argues that 27% of all twins in this species are MZ pairs. In this protected species, where twinning is commonplace (~50% of newborns are twins), the probable existence of frequent MZ twinning has ramifications for breeding programs aimed to maximize genetic diversity, and suggests that twin studies in a species other than human could have potential as a medical research tool.

Interspecific Semantic Alarm Call Recognition in the Solitary Sahamalaza Sportive Lemur, Lepilemur sahamalazensis

PubMed Central

Seiler, Melanie; Schwitzer, Christoph; Gamba, Marco; Holderied, Marc W.

2013-01-01

As alarm calls indicate the presence of predators, the correct interpretation of alarm calls, including those of other species, is essential for predator avoidance. Conversely, communication calls of other species might indicate the perceived absence of a predator and hence allow a reduction in vigilance. This “eavesdropping” was demonstrated in birds and mammals, including lemur species. Interspecific communication between taxonomic groups has so far been reported in some reptiles and mammals, including three primate species. So far, neither semantic nor interspecific communication has been tested in a solitary and nocturnal lemur species. The aim of this study was to investigate if the nocturnal and solitary Sahamalaza sportive lemur, Lepilemur sahamalazensis, is able to access semantic information of sympatric species. During the day, this species faces the risk of falling prey to aerial and terrestrial predators and therefore shows high levels of vigilance. We presented alarm calls of the crested coua, the Madagascar magpie-robin and aerial, terrestrial and agitation alarm calls of the blue-eyed black lemur to 19 individual Sahamalaza sportive lemurs resting in tree holes. Songs of both bird species’ and contact calls of the blue-eyed black lemur were used as a control. After alarm calls of crested coua, Madagascar magpie-robin and aerial alarm of the blue-eyed black lemur, the lemurs scanned up and their vigilance increased significantly. After presentation of terrestrial alarm and agitation calls of the blue-eyed black lemur, the animals did not show significant changes in scanning direction or in the duration of vigilance. Sportive lemur vigilance decreased after playbacks of songs of the bird species and contact calls of blue-eyed black lemurs. Our results indicate that the Sahamalaza sportive lemur is capable of using information on predator presence as well as predator type of different sympatric species, using their referential signals to detect

"Life history space": a multivariate analysis of life history variation in extant and extinct Malagasy lemurs.

PubMed

Catlett, Kierstin K; Schwartz, Gary T; Godfrey, Laurie R; Jungers, William L

2010-07-01

Studies of primate life history variation are constrained by the fact that all large-bodied extant primates are haplorhines. However, large-bodied strepsirrhines recently existed. If we can extract life history information from their skeletons, these species can contribute to our understanding of primate life history variation. This is particularly important in light of new critiques of the classic "fast-slow continuum" as a descriptor of variation in life history profiles across mammals in general. We use established dental histological methods to estimate gestation length and age at weaning for five extinct lemur species. On the basis of these estimates, we reconstruct minimum interbirth intervals and maximum reproductive rates. We utilize principal components analysis to create a multivariate "life history space" that captures the relationships among reproductive parameters and brain and body size in extinct and extant lemurs. Our data show that, whereas large-bodied extinct lemurs can be described as "slow" in some fashion, they also varied greatly in their life history profiles. Those with relatively large brains also weaned their offspring late and had long interbirth intervals. These were not the largest of extinct lemurs. Thus, we distinguish size-related life history variation from variation that linked more strongly to ecological factors. Because all lemur species larger than 10 kg, regardless of life history profile, succumbed to extinction after humans arrived in Madagascar, we argue that large body size increased the probability of extinction independently of reproductive rate. We also provide some evidence that, among lemurs, brain size predicts reproductive rate better than body size. (c) 2010 Wiley-Liss, Inc.

Systemic effects of Leucaena leucocephala ingestion on ringtailed lemurs (Lemur catta) at Berenty Reserve, Madagascar.

PubMed

Crawford, Graham; Puschner, Birgit; Affolter, Verena; Stalis, Ilse; Davidson, Autumn; Baker, Tomas; Tahara, John; Jolly, Alison; Ostapak, Susan

2015-06-01

Leucaena (Leucaena leucocephala) is a leguminous tree that is nutritious forage for domestic livestock when ingested in limited amounts. Unfortunately, leucaena contains mimosine, a plant amino acid, that can be toxic when ingested at higher concentrations. Reported toxic effects include alopecia (fur loss), poor body condition, infertility, low birth weight, thyroid gland dysfunction, and organ toxicity. Originally native to Mexico and Central America, leucaena has been introduced throughout the tropics, including Berenty Reserve, Madagascar where it was planted as supplemental browse for livestock. In Berenty, a seasonal syndrome of alopecia in ringtailed lemurs (Lemur catta) is associated with eating leucaena. Although much is known about the toxic effects of leucaena and mimosine on domestic animals and humans, the systemic effects on wildlife had not been studied. In a comparison of lemurs that include leucaena in their diet and those that do not, we found that animals that ingest leucaena absorb mimosine but that ingestion does not affect body condition, cause kidney or liver toxicity, or affect the intestinal tract. Alopecia is due to mimosine's interference of the hair follicle cycle. Leucaena ingestion is associated with higher serum albumin, α-tocopherol, and thyroxine concentrations, suggesting that leucaena may provide some nutritional benefit and that lemurs can detoxify and convert mimosine to a thyroid stimulating metabolite. The primary conservation consequence of leucaena ingestion at Berenty may be increased infant mortality due to the infants' inability cling to their alopecic mothers. The widespread introduction of leucaena throughout the tropics and its rapid spread in secondary forest conditions mean that many other leaf-eating mammals may be including this tree in their diet. Thus, exposure to leucaena should be considered when wildlife health is being evaluated, and the potential effects on wildlife health should be considered when

Knowledgeable Lemurs Become More Central in Social Networks.

PubMed

Kulahci, Ipek G; Ghazanfar, Asif A; Rubenstein, Daniel I

2018-04-23

Strong relationships exist between social connections and information transmission [1-9], where individuals' network position plays a key role in whether or not they acquire novel information [2, 3, 5, 6]. The relationships between social connections and information acquisition may be bidirectional if learning novel information, in addition to being influenced by it, influences network position. Individuals who acquire information quickly and use it frequently may receive more affiliative behaviors [10, 11] and may thus have a central network position. However, the potential influence of learning on network centrality has not been theoretically or empirically addressed. To bridge this epistemic gap, we investigated whether ring-tailed lemurs' (Lemur catta) centrality in affiliation networks changed after they learned how to solve a novel foraging task. Lemurs who had frequently initiated interactions and approached conspecifics before the learning experiment were more likely to observe and learn the task solution. Comparing social networks before and after the learning experiment revealed that the frequently observed lemurs received more affiliative behaviors than they did before-they became more central after the experiment. This change persisted even after the task was removed and was not caused by the observed lemurs initiating more affiliative behaviors. Consequently, quantifying received and initiated interactions separately provides unique insights into the relationships between learning and centrality. While the factors that influence network position are not fully understood, our results suggest that individual differences in learning and becoming successful can play a major role in social centrality, especially when learning from others is advantageous. Copyright © 2018 Elsevier Ltd. All rights reserved.

Transitive inference in two lemur species (Eulemur macaco and Eulemur fulvus).

PubMed

Tromp, D; Meunier, H; Roeder, J J

2015-03-01

When confronted with tasks involving reasoning instead of simple learning through trial and error, lemurs appeared to be less competent than simians. Our study aims to investigate lemurs' capability for transitive inference, a form of deductive reasoning in which the subject deduces logical conclusions from preliminary information. Transitive inference may have an adaptative function, especially in species living in large, complex social groups and is proposed to play a major role in rank estimation and establishment of dominance hierarchies. We proposed to test the capacities of reasoning using transitive inference in two species of lemurs, the brown lemur (Eulemur fulvus) and the black lemur (Eulemur macaco), both living in multimale-multifemale societies. For that purpose, we designed an original setup providing, for the first time in this kind of cognitive task, pictures of conspecifics' faces as stimuli. Subjects were trained to differentiate six photographs of unknown conspecifics named randomly from A to F to establish the order A > B > C > D > E > F and select consistently the highest-ranking photograph in five adjacent pairs AB, BC, CD, DE, and EF. Then lemurs were presented with the same adjacent pairs and three new and non-adjacent pairs BD, BE, CE. The results showed that all subjects correctly selected the highest-ranking photograph in every non-adjacent pair, reflecting lemurs' capacity for transitive inference. Our results are discussed in the context of the still debated current theories about the mechanisms underlying this specific capacity. © 2014 Wiley Periodicals, Inc.

Rate of digesta passage in the philippine flying lemur, Cynocephalus volans.

PubMed

Wischusen, E W; Ingle, N; Richmond, M E

1994-01-01

The rate of digesta passage was measured in five captive Philippine flying lemurs (Cynocephalus volans). These animals were force fed capsules containing known quantities of either particulate or soluble markers. The volumes of the gastrointestinal tracts of three flying lemurs were determined based on the wet weight of the contents of each section of the gut. The mean rate of digesta passage was 14.37 +/- 3.31 h when determined using the particulate marker and 21.9 +/- 0.03 h when determined using the soluble marker. The values based on the particulate marker are between 2% and 10% of similar values for other arboreal folivores. The morphology of the gastrointestinal system of the Philippine flying lemur is similar to that of other hindgut fermenters. Flying lemurs have a simple stomach and a large caecum. The total gut capacity of the Philippine flying lemur is similar to that of other herbivores, but is slightly smaller than that of either the koala (Phascolarctos cinereus), a hindgut fermenter, or the three-toed sloth (Bradypus variegatus), a foregut fermenter. These data suggest that flying lemurs deal with the problems of a folivorous diet very differently than some other arboreal mammals. Phascolarctos cinereus and Bradypus variegatus may represent one extreme with Cynocephalus volans representing the other extreme along a continuum of foraging strategies that are compatible with the arboreal folivore lifestyle.

Genetic wealth, population health: Major histocompatibility complex variation in captive and wild ring-tailed lemurs (Lemur catta).

PubMed

Grogan, Kathleen E; Sauther, Michelle L; Cuozzo, Frank P; Drea, Christine M

2017-10-01

Across species, diversity at the major histocompatibility complex (MHC) is critical to individual disease resistance and, hence, to population health; however, MHC diversity can be reduced in small, fragmented, or isolated populations. Given the need for comparative studies of functional genetic diversity, we investigated whether MHC diversity differs between populations which are open, that is experiencing gene flow, versus populations which are closed, that is isolated from other populations. Using the endangered ring-tailed lemur ( Lemur catta ) as a model, we compared two populations under long-term study: a relatively "open," wild population ( n  = 180) derived from Bezà Mahafaly Special Reserve, Madagascar (2003-2013) and a "closed," captive population ( n  = 121) derived from the Duke Lemur Center (DLC, 1980-2013) and from the Indianapolis and Cincinnati Zoos (2012). For all animals, we assessed MHC-DRB diversity and, across populations, we compared the number of unique MHC-DRB alleles and their distributions. Wild individuals possessed more MHC-DRB alleles than did captive individuals, and overall, the wild population had more unique MHC-DRB alleles that were more evenly distributed than did the captive population. Despite management efforts to maintain or increase genetic diversity in the DLC population, MHC diversity remained static from 1980 to 2010. Since 2010, however, captive-breeding efforts resulted in the MHC diversity of offspring increasing to a level commensurate with that found in wild individuals. Therefore, loss of genetic diversity in lemurs, owing to small founder populations or reduced gene flow, can be mitigated by managed breeding efforts. Quantifying MHC diversity within individuals and between populations is the necessary first step to identifying potential improvements to captive management and conservation plans.

Alveolar hydatidosis in a gorilla and a ring-tailed lemur in Japan.

PubMed

Kondo, H; Wada, Y; Bando, G; Kosuge, M; Yagi, K; Oku, Y

1996-05-01

Alveolar hydatidosis by Echinococcus multilocularis (Em) infection occurred on a 22-year-old (approx.) male gorilla (Gorilla gorilla) and a 4-year-old female ring-tailed lemur (Lemur catta) in a zoo, in Hokkaido, Japan. Case 1: The gorilla presented neurologic signs in course of nine months and died. Pathologically, alveolar hydatid lesions were found in the liver, the liver-associated lymph nodes, the cerebrum, and the lungs. A protoscolex was found only in one hepatic cyst. Case 2: In the lemur, large masses of hydatide cysts were found on the liver and at the lung-associated lymph nodes. Cysts contained numerous calcareous corpuscles and protoscolices. The lemur appears a favorable intermediate-host for Em. The identification of Em in both cases were confirmed by PCR.

Social thermoregulation in redfronted lemurs (Eulemur fulvus rufus).

PubMed

Ostner, Julia

2002-01-01

Pronounced seasonality, with temperatures dropping as low as 5 degrees C during the dry season, has led to the hypothesis that Malagasy lemurs face cold stress and respond to this by inactivity and social thermoregulation, i.e. resting in tight body contact with conspecifics. Compared to anthropoids, lemur groups are comprised of an unusually high number of males, leading to an even or slightly male-biased adult sex ratio. According to one hypothesis, females may benefit from these surplus males in their groups if males huddle with females. The results of this study on redfronted lemurs (Eulemur fulvus rufus) in Kirindy Forest, Madagascar revealed that the animals indeed responded to cold ambient temperatures by increased inactivity and the formation of huddling groups. However, surplus males did not participate more frequently than expected in huddling groups with females and females do not, therefore, benefit from the high number of males in their groups by increased social thermoregulation.

Seroprevalence of Toxoplasma gondii, Sarcocystis neurona, and Encephalitozoon cuniculi in three species of lemurs from St. Catherines Island, GA, USA.

PubMed

Yabsley, Michael J; Jordan, Carly N; Mitchell, Sheila M; Norton, Terry M; Lindsay, David S

2007-03-15

In the current study, we determined the seroprevalence of Toxoplasma gondii, Sarcocystis neurona, and Encephalitozoon cuniculi in three species of lemurs from St. Catherines Island, Georgia. Serum samples were tested from 52 ring-tailed lemurs (Lemur catta), six blue-eyed black lemurs (Eulemur macaco flavifrons), and four black and white ruffed lemurs (Varecia variegata variegata) using an agglutination assay. Three ring-tailed lemurs (5.8%) were positive for T. gondii (titer of 1:50); one ring-tailed lemur (1.9%) and one black and white ruffed lemur (25%) were positive for S. neurona (titers of 1:1000); and one ring-tailed lemur (1.9%) was positive for E. cuniculi (titer of 1:400). All blue-eyed black lemurs were negative for antibodies to T. gondii, S. neurona, and E. cuniculi. This is the first detection of antibodies to T. gondii in ring-tailed lemurs and antibodies to S. neurona and E. cuniculi in any species of prosimian.

"I am going to groom you": Multiple forms of play fighting in gray mouse lemurs (Microcebus murinus).

PubMed

Pellis, Sergio M; Pellis, Vivien C

2018-02-01

Play fighting is a commonly reported form of play that involves competitive interactions that generally do not escalate to serious fighting. Although in many species what are competed over are the body targets that are bitten or struck in serious fighting, for many others, the competition can be over other forms of contact, such as sex, social grooming, and predation. In primates, the most detailed studies have been of species such as Old World monkeys, that engage in play fighting that simulates serious fighting, but reports of a number of others, especially among nocturnal prosimians, have noted that play fighting can also involve simulation of sex and grooming. The present study on captive born gray mouse lemurs ( Microcebus murinus ) provides a quantitative assessment of the relative engagement by juveniles in play fighting involving agonistic and amicable targets. About 80% of play fighting involves competing to groom or mount one another, with a minority involving competing to bite. That these forms of play fighting may be distinct from one another is suggested by the finding that attack on one target does not lead to counterattack on another. The findings are discussed in terms of the evolution and mechanisms underlying play fighting in primates and more widely among animals. (PsycINFO Database Record (c) 2018 APA, all rights reserved).

Edge effects and their influence on lemur density and distribution in Southeast Madagascar.

PubMed

Lehman, Shawn M; Rajaonson, Andry; Day, Sabine

2006-02-01

Edge effects are caused by the penetration of abiotic and biotic conditions from the matrix into forest interiors. Although edge effects influence the biogeography of many tropical organisms, they have not been studied directly in primates. Edge effects are particularly relevant to lemurs due to the loss of 80-90% of forests in Madagascar. In this study, data are presented on how biotic edge effects influenced the distribution and density of lemurs in the Vohibola III Classified Forest in southeastern Madagascar. In total, 415 lemur surveys were conducted during June-October 2003 and May-September 2004 along six 1,250-m transects that ran perpendicular to the forest edge. Data were also collected on lemur food trees along the six transects (density, height, diameter at breast height, area, volume, and distance to forest edge). Four nocturnal species (Avahi laniger, Cheirogaleus major, Lepilemur microdon, and Microcebus rufus) and four diurnal species (Eulemur rubriventer, Eulemur fulvus rufus, Hapalemur grisesus griseus, and Propithecus diadema edwardsi) were sighted during surveys. Regression analyses of lemur densities as a function of distance to forest edge provided edge tolerances for A. laniger (edge-tolerant), M. rufus (edge-tolerant), E. rubriventer (edge-tolerant or omnipresent), and H. g. griseus (omnipresent). The density and distribution of M. rufus and their foods trees were correlated. Edge-related variations in food quality and predation pressures may also be influencing lemurs in Vohibola III. Tolerance for edge effects may explain, in part, how lemurs have survived extreme habitat loss and forest fragmentation in southeastern Madagascar.

LEMUR: Large European Module for Solar Ultraviolet Research

NASA Technical Reports Server (NTRS)

Teriaca, Luca; Vincenzo, Andretta; Auchere, Frederic; Brown, Charles M.; Buchlin, Eric; Cauzzi, Gianna; Culhane, J. Len; Curdt, Werner; Davila, Joseph M.; Del Zanna, Giulio;

Opsin gene polymorphism predicts trichromacy in a cathemeral lemur.

PubMed

Veilleux, Carrie C; Bolnick, Deborah A

2009-01-01

Recent research has identified polymorphic trichromacy in three diurnal strepsirrhines: Coquerel's sifaka (Propithecus coquereli), black and white ruffed lemurs (Varecia variegata), and red ruffed lemurs (V. rubra). Current hypotheses suggest that the transitions to diurnality experienced by Propithecus and Varecia were necessary precursors to their independent acquisitions of trichromacy. Accordingly, cathemeral lemurs are thought to lack the M/L opsin gene polymorphism necessary for trichromacy. In this study, the M/L opsin gene was sequenced in ten cathemeral blue-eyed black lemurs (Eulemur macaco flavifrons). This analysis identified a polymorphism identical to that of other trichromatic strepsirrhines at the critical amino acid position 285 in exon 5 of the M/L opsin gene. Thus, polymorphic trichromacy is likely present in at least one cathemeral Eulemur species, suggesting that strict diurnality is not necessary for trichromacy. The presence of trichromacy in E. m. flavifrons suggests that a re-evaluation of current hypotheses regarding the evolution of strepsirrhine trichromacy may be necessary. Although the M/L opsin polymorphism may have been independently acquired three times in the lemurid-indriid clade, the distribution of opsin alleles in lemurids and indriids may also be consistent with a common origin of trichromacy in the last common ancestor of either the lemurids or the lemurid-indriid clade. (c) 2008 Wiley-Liss, Inc.

Lemurs and macaques show similar numerical sensitivity.

PubMed

Jones, Sarah M; Pearson, John; DeWind, Nicholas K; Paulsen, David; Tenekedjieva, Ana-Maria; Brannon, Elizabeth M

2014-05-01

We investigated the precision of the approximate number system (ANS) in three lemur species (Lemur catta, Eulemur mongoz, and Eulemur macaco flavifrons), one Old World monkey species (Macaca mulatta) and humans (Homo sapiens). In Experiment 1, four individuals of each nonhuman primate species were trained to select the numerically larger of two visual arrays on a touchscreen. We estimated numerical acuity by modeling Weber fractions (w) and found quantitatively equivalent performance among all four nonhuman primate species. In Experiment 2, we tested adult humans in a similar procedure, and they outperformed the four nonhuman species but showed qualitatively similar performance. These results indicate that the ANS is conserved over the primate order.

A Genome Sequence Resource for the Aye-Aye (Daubentonia madagascariensis), a Nocturnal Lemur from Madagascar

PubMed Central

Perry, George H.; Reeves, Darryl; Melsted, Páll; Ratan, Aakrosh; Miller, Webb; Michelini, Katelyn; Louis, Edward E.; Pritchard, Jonathan K.; Mason, Christopher E.; Gilad, Yoav

2012-01-01

We present a high-coverage draft genome assembly of the aye-aye (Daubentonia madagascariensis), a highly unusual nocturnal primate from Madagascar. Our assembly totals ∼3.0 billion bp (3.0 Gb), roughly the size of the human genome, comprised of ∼2.6 million scaffolds (N50 scaffold size = 13,597 bp) based on short paired-end sequencing reads. We compared the aye-aye genome sequence data with four other published primate genomes (human, chimpanzee, orangutan, and rhesus macaque) as well as with the mouse and dog genomes as nonprimate outgroups. Unexpectedly, we observed strong evidence for a relatively slow substitution rate in the aye-aye lineage compared with these and other primates. In fact, the aye-aye branch length is estimated to be ∼10% shorter than that of the human lineage, which is known for its low substitution rate. This finding may be explained, in part, by the protracted aye-aye life-history pattern, including late weaning and age of first reproduction relative to other lemurs. Additionally, the availability of this draft lemur genome sequence allowed us to polarize nucleotide and protein sequence changes to the ancestral primate lineage—a critical period in primate evolution, for which the relevant fossil record is sparse. Finally, we identified 293,800 high-confidence single nucleotide polymorphisms in the donor individual for our aye-aye genome sequence, a captive-born individual from two wild-born parents. The resulting heterozygosity estimate of 0.051% is the lowest of any primate studied to date, which is understandable considering the aye-aye's extensive home-range size and relatively low population densities. Yet this level of genetic diversity also suggests that conservation efforts benefiting this unusual species should be prioritized, especially in the face of the accelerating degradation and fragmentation of Madagascar's forests. PMID:22155688

A genome sequence resource for the aye-aye (Daubentonia madagascariensis), a nocturnal lemur from Madagascar.

PubMed

Perry, George H; Reeves, Darryl; Melsted, Páll; Ratan, Aakrosh; Miller, Webb; Michelini, Katelyn; Louis, Edward E; Pritchard, Jonathan K; Mason, Christopher E; Gilad, Yoav

2012-01-01

We present a high-coverage draft genome assembly of the aye-aye (Daubentonia madagascariensis), a highly unusual nocturnal primate from Madagascar. Our assembly totals ~3.0 billion bp (3.0 Gb), roughly the size of the human genome, comprised of ~2.6 million scaffolds (N50 scaffold size = 13,597 bp) based on short paired-end sequencing reads. We compared the aye-aye genome sequence data with four other published primate genomes (human, chimpanzee, orangutan, and rhesus macaque) as well as with the mouse and dog genomes as nonprimate outgroups. Unexpectedly, we observed strong evidence for a relatively slow substitution rate in the aye-aye lineage compared with these and other primates. In fact, the aye-aye branch length is estimated to be ~10% shorter than that of the human lineage, which is known for its low substitution rate. This finding may be explained, in part, by the protracted aye-aye life-history pattern, including late weaning and age of first reproduction relative to other lemurs. Additionally, the availability of this draft lemur genome sequence allowed us to polarize nucleotide and protein sequence changes to the ancestral primate lineage-a critical period in primate evolution, for which the relevant fossil record is sparse. Finally, we identified 293,800 high-confidence single nucleotide polymorphisms in the donor individual for our aye-aye genome sequence, a captive-born individual from two wild-born parents. The resulting heterozygosity estimate of 0.051% is the lowest of any primate studied to date, which is understandable considering the aye-aye's extensive home-range size and relatively low population densities. Yet this level of genetic diversity also suggests that conservation efforts benefiting this unusual species should be prioritized, especially in the face of the accelerating degradation and fragmentation of Madagascar's forests.

Better Few than Hungry: Flexible Feeding Ecology of Collared Lemurs Eulemur collaris in Littoral Forest Fragments

PubMed Central

Donati, Giuseppe; Kesch, Kristina; Ndremifidy, Kelard; Schmidt, Stacey L.; Ramanamanjato, Jean-Baptiste; Borgognini-Tarli, Silvana M.; Ganzhorn, Joerg U.

2011-01-01

Background Frugivorous primates are known to encounter many problems to cope with habitat degradation, due to the fluctuating spatial and temporal distribution of their food resources. Since lemur communities evolved strategies to deal with periods of food scarcity, these primates are expected to be naturally adapted to fluctuating ecological conditions and to tolerate a certain degree of habitat changes. However, behavioral and ecological strategies adopted by frugivorous lemurs to survive in secondary habitats have been little investigated. Here, we compared the behavioral ecology of collared lemurs (Eulemur collaris) in a degraded fragment of littoral forest of south-east Madagascar, Mandena, with that of their conspecifics in a more intact habitat, Sainte Luce. Methodology/Principal Findings Lemur groups in Mandena and in Sainte Luce were censused in 2004/2007 and in 2000, respectively. Data were collected via instantaneous sampling on five lemur groups totaling 1,698 observation hours. The Shannon index was used to determine dietary diversity and nutritional analyses were conducted to assess food quality. All feeding trees were identified and measured, and ranging areas determined via the minimum convex polygon. In the degraded area lemurs were able to modify several aspects of their feeding strategies by decreasing group size and by increasing feeding time, ranging areas, and number of feeding trees. The above strategies were apparently able to counteract a clear reduction in both food quality and size of feeding trees. Conclusions/Significance Our findings indicate that collared lemurs in littoral forest fragments modified their behavior to cope with the pressures of fluctuating resource availability. The observed flexibility is likely to be an adaptation to Malagasy rainforests, which are known to undergo periods of fruit scarcity and low productivity. These results should be carefully considered when relocating lemurs or when selecting suitable areas for

A glance to the past: subfossils, stable isotopes, seed dispersal, and lemur species loss in Southern Madagascar.

PubMed

Crowley, Brooke E; Godfrey, Laurie R; Irwin, Mitchell T

2011-01-01

The Spiny Thicket Ecoregion (STE) of Southern and southwestern Madagascar was recently home to numerous giant lemurs and other "megafauna," including pygmy hippopotamuses, giant tortoises, elephant birds, and large euplerid carnivores. Following the arrival of humans more than 2,000 years ago, dramatic extinctions occurred. Only one-third of the lemur species which earlier occupied the STE survive today; other taxa suffered even greater losses. We use stable isotope biogeochemistry to reconstruct past diets and habitat preferences of the recently extinct lemurs of the STE. We show that the extinct lemurs occupied a wide range of niches, often distinct from those filled by coeval non-primates. Many of the now-extinct lemurs regularly exploited habitats that were drier than the gallery forests in which the remaining lemurs of this ecoregion are most often protected and studied. Most fed predominantly on C3 plants and some were likely the main dispersers of the large seeds of native C3 trees; others included CAM and/or C4 plants in their diets. These new data suggest that the recent extinctions have likely had significant ecological ramifications for the communities and ecosystems of Southern and southwestern Madagascar. © 2010 Wiley-Liss, Inc.

Anatomy, histology, and ultrasonography of the normal adrenal gland in brown lemur: Eulemur fulvus.

PubMed

Raharison, Fidiniaina; Bourges Abella, Nathalie; Sautet, Jean; Deviers, Alexandra; Mogicato, Giovanni

2017-04-01

The medical care currently to brown lemurs (Eulemur fulvus) is limited by a lack of knowledge of their anatomy. The aim of this study was to describe the anatomy and histology and obtain ultrasonographic measurements of normal adrenal glands in these animals. The adrenal glands of four lemurs cadavers were used for the anatomical and histological studies, and those of 15 anesthetized lemurs were examined by ultrasonography. Anatomically, the adrenal glands of brown lemurs are comparable to those of other species. The histological findings showed that the cortex is organized into three distinct layers, whereas most domestic mammals have an additional zone. The surface area of the adrenal glands increased with body weight, and the area of the right adrenal was slightly larger than the left. We suggest using ultrasonography to aid the etiological diagnosis of behavioral abnormalities that might be due to dysfunctions of the adrenal gland. © 2017 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Exploring the Role of Wealth and Religion on the Ownership of Captive Lemurs in Madagascar Using Qualitative and Quantitative Data.

PubMed

Reuter, Kim E; Clarke, Tara A; LaFleur, Marni; Ratsimbazafy, Jonah; Holiniaina Kjeldgaard, Fabiola; Rodriguez, Lucia; Schaeffer, Toby; Schaefer, Melissa S

2018-01-01

Primates are kept as pets for various reasons including as indicators of wealth. Ownership of primates can also be influenced by religion. In Madagascar, thousands of lemurs are kept as pets, but the roles of wealth and religion in the ownership of captive lemurs have not been explored. We use quantitative and qualitative data to examine these aspects of ownership. Quantitative data were collected (July to August 2016) in households (n = 596) of 12 urban and rural towns in Madagascar using semi-structured interviews. International standards for research ethics were followed. Research was approved by an ethics oversight committee. We also opportunistically visited 13 religious facilities. Qualitative data were used to frame the context of the quantitative data. We found that pet lemur owners do not speak about their lemurs as a symbol of wealth, but non-owners associate pet lemurs with wealth. Therefore, status/wealth may be a motivating factor in the ownership of pet lemurs. We also found evidence that Catholic entities in Madagascar sometimes take in captive lemurs when the owner can no longer care for the animal (being viewed as animal-friendly institutions). However, we did not find evidence of religion (institutional or traditional) influencing the ownership of pet lemurs. © 2018 S. Karger AG, Basel.

Illegal captive lemurs in Madagascar: Comparing the use of online and in-person data collection methods.

PubMed

Reuter, Kim E; Schaefer, Melissa S

2017-11-01

Although it is illegal to capture, sell, and trade lemurs, the live capture of lemurs in Madagascar is ongoing and may have impacted over 28,000 lemurs between 2010 and 2013. Only one study has examined this trade and did so using in-person interviews in northern Madagascar. The current study sought to expand this existing dataset and examine the comparability of online surveys to more traditional on-location data collection methods. In this study, we collected data through a web-based survey resulting in 302 sightings of 685 captive lemurs. We also collected data from 171 hotel and 43 restaurant websites and social media profiles. Survey submissions included sightings of 30 species from 10 genera, nearly twice as many species as identified via the in-person interviews. Lemur catta, Varecia variegata, and Eulemur fulvus were the most common species sighted in captivity. Captive lemurs were reported in 19 of Madagascar's 22 administrative regions and most were seen in urban areas near their habitat ranges. This represents a wider geographic distribution of captive lemurs than previously found through in-person interviews. The online survey results were broadly similar to those of the in-person surveys though greater in species and geographic diversity demonstrating advantages to the use of online surveys. The online research methods were low in cost (USD $100) compared to on-location data collection (USD $12,000). Identified disadvantages included sample bias; most of the respondents to the online survey were researchers and many captive sightings were near study sites. The results illustrate the benefits of incorporating a social science approach using online surveys as a complement to traditional fieldwork. Am. J. Primatol. 79:e22541, 2017. © 2016 Wiley Periodicals, Inc. © 2016 Wiley Periodicals, Inc.

The microbiome of Haemaphysalis lemuris (Acari: Ixodidae), a possible vector of pathogens of endangered lemur species in Madagascar.

PubMed

Lado, Paula; Qurollo, Barbara; Williams, Cathy; Junge, Randall; Klompen, Hans

2018-05-02

Lemurs are primate species that are endemic to Madagascar. At present, about 90% of lemur species are endangered, and 5 species are among the 25 most endangered primates worldwide. Health status is a major factor impacting the viability of wild populations of many endangered species including lemurs. Given this context, we analyzed the microbiome of 24 specimens of Haemaphysalis lemuris, the most common tick parasitizing lemurs in their native habitats. Ticks were collected from 6 lemur species and microbiomes analyzed using next-generation sequencing. Our results show that the H. lemuris microbiome is highly diverse, including over 500 taxa, 267 of which were identified to genus level. Analysis of the microbiome also shows that there is a distinct "host" (lemur species) component when explaining the differences among and between microbial communities of H. lemuris. This "host" component seems to overwhelm any "locality" (geographic origin of the sample) component. In addition to the microbiome data, targeted PCR was used to test for the presence of three pathogens recently detected in the blood of wild lemurs: Borrelia sp., Candidatus Neoehrlichia sp., and Babesia sp. Overall, the presence of DNA of Rickettsia spp., Bartonella spp., Francisella spp., and a Babesia sp., in H. lemuris, is consistent with the hypothesis that these ectoparasites may act as vector for these pathogens. Further studies assessing vector competence are needed to confirm this hypothesis. Copyright © 2018 Elsevier GmbH. All rights reserved.

Comparison of conservation metrics in a case study of lemurs.

PubMed

Gudde, Renske; Venditti, Chris

2016-12-01

Conservation planning is important to protect species from going extinct now that natural habitats are decreasing owing to human activity and climate change. However, there is considerable controversy in choosing appropriate metrics to weigh the value of species and geographic regions. For example, the added value of phylogenetic conservation-selection criteria remains disputed because high correlations between them and the nonphylogenetic criteria of species richness have been reported. We evaluated the commonly used conservation metrics species richness, endemism, phylogenetic diversity (PD), and phylogenetic endemism (PE) in a case study on lemurs of Madagascar. This enabled us to identify the conservation target of each metric and consider how they may be used in future conservation planning. We also devised a novel metric that uses a phylogeny scaled according to the rate of phenotypic evolution as a proxy for a species' ability to adapt to change. High rates of evolution may indicate generalization or specialization. Both specialization and low rates of evolution may result in an inability to adapt to changing environments. We examined conservation priorities by using the inverse of the rate of body mass evolution to account for species with low rates of evolution. In line with previous work, we found high correlations among species richness and PD (r = 0.96), and endemism and PE (r = 0.82) in Malagasy lemurs. Phylogenetic endemism in combination with rates of evolution and their inverse prioritized grid cells containing highly endemic and specialized lemurs at risk of extinction, such as Avahi occidentalis and Lepilemur edwardsi, 2 endangered lemurs with high rates of phenotypic evolution and low-quality diets, and Hapalemur aureus, a critically endangered species with a low rate of body mass evolution and a diet consisting of very high doses of cyanide. © 2016 Society for Conservation Biology.

Fatal infection with Taenia martis metacestodes in a ring-tailed lemur (Lemur catta) living in an Italian zoological garden.

PubMed

De Liberato, Claudio; Berrilli, Federica; Meoli, Roberta; Friedrich, Klaus G; Di Cerbo, Pilar; Cocumelli, Cristiano; Eleni, Claudia

2014-10-01

A case of fatal infection caused by larval forms of Taenia martis in a ring-tailed lemur (Lemur catta) living in the Rome zoological garden is described. The animal, living in a semi-natural pen with other 15 conspecific individuals and being fed with fresh fruit and vegetables, yoghurt and eggs, was transported to the Istituto Zooprofilattico of Rome for post-mortem examination. The anamnesis included, ten days before the death, apathy, lack of appetite, abdominal distension and diarrhoea. A severe exudative fibrinous-purulent peritonitis with numerous adhesions between the abdominal wall and the bowel loops was detected. After intestine removal, two free and viable, 4 cm long, whitish, leaf-like parasitic forms were pinpointed. Macroscopic examination of the two parasites allowed their identification as larval stages of cestodes, identified via molecular analysis as T. martis metacestodes. This report represents the first record of T. martis infection in the host species and in a zoological garden and for the pathological relevance of the infection. Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.

Anatomy and ultrasonography of the normal kidney in brown lemurs: Eulemur fulvus.

PubMed

Raharison, Fidiniaina; Mogicato, Giovanni; Sautet, Jean

2009-08-01

The purpose of this study is to describe the anatomy and obtain echographic measurements of normal kidneys in brown lemurs (Eulemur fulvus). The anatomical findings show that brown lemur kidneys are comparable to those of rats except for an elongated papilla. The kidneys of 16 (7 females and 9 males) lemurs were examined with two-dimensional and power Doppler ultrasonography under general anesthesia. Morphometrically, the left and right kidney surface areas are comparable (3.29 and 3.51 cm(2)). Kidney area has a significant linear correlation with body weight. Echo-Doppler findings show that the mean renal arterial blood flow speeds for the left and right kidneys are comparable (0.70 and 0.73 m/s). However, flow speed is higher in the male (0.79 m/s) than in the female (0.60 m/s). The renal arterial diameters are between 1.0 and 1.8 mm. The fact that anesthesia can have hemodynamic effects on renal vasculature should be taken into consideration when assessing these echographic results.

Detection of virus-like particles in the liver of black and white ruffed lemurs with hepatitis.

PubMed

Worley, Michael B; Stalis, Ilse H

2002-04-01

Two young black and white ruffed lemurs (Varecia variegata variegata) died at the San Diego Zoo (San Diego, California, USA) with extensive liver lesions suggestive of acute viral infection. Immunoassays performed to detect hepatitis B virus (HBV) markers were negative. Polymerase chain reaction (PCR) primers overlapping the HBV core gene produced an amplicon of approximately 411 base pairs (bp) from serum DNA of a HBV-positive western lowland gorilla (Gorilla gorilla gorilla) but not from serum DNA of either lemur. Cesium chloride gradient fractions of liver homogenates from both lemurs contained a peak protein fraction with a density of 1.18 g/cm3. Electron microscopic analysis of fraction contents, concentrated by ultracentrifulgation, revealed numerous pleomorphic, spherical particles varying in diameter from 16-25 nm. In one of the lemurs, this peak fraction also contained a double-shelled virus-like particle 47-50 nm in diameter. The size, morphology, and density of these particles suggest they are members of the Hepadnaviridae, a group of hepatotropic DNA-genome viruses for which HBV is the prototype.

DNA from extinct giant lemurs links archaeolemurids to extant indriids.

PubMed

Orlando, Ludovic; Calvignac, Sébastien; Schnebelen, Céline; Douady, Christophe J; Godfrey, Laurie R; Hänni, Catherine

2008-04-28

Although today 15% of living primates are endemic to Madagascar, their diversity was even greater in the recent past since dozens of extinct species have been recovered from Holocene excavation sites. Among them were the so-called "giant lemurs" some of which weighed up to 160 kg. Although extensively studied, the phylogenetic relationships between extinct and extant lemurs are still difficult to decipher, mainly due to morphological specializations that reflect ecology more than phylogeny, resulting in rampant homoplasy. Ancient DNA recovered from subfossils recently supported a sister relationship between giant "sloth" lemurs and extant indriids and helped to revise the phylogenetic position of Megaladapis edwardsi among lemuriformes, but several taxa - such as the Archaeolemuridae - still await analysis. We therefore used ancient DNA technology to address the phylogenetic status of the two archaeolemurid genera (Archaeolemur and Hadropithecus). Despite poor DNA preservation conditions in subtropical environments, we managed to recover 94- to 539-bp sequences for two mitochondrial genes among 5 subfossil samples. This new sequence information provides evidence for the proximity of Archaeolemur and Hadropithecus to extant indriids, in agreement with earlier assessments of their taxonomic status (Primates, Indrioidea) and in contrast to recent suggestions of a closer relationship to the Lemuridae made on the basis of analyses of dental developmental and postcranial characters. These data provide new insights into the evolution of the locomotor apparatus among lemurids and indriids.

Sight or Scent: Lemur Sensory Reliance in Detecting Food Quality Varies with Feeding Ecology

PubMed Central

Rushmore, Julie; Leonhardt, Sara D.; Drea, Christine M.

2012-01-01

Visual and olfactory cues provide important information to foragers, yet we know little about species differences in sensory reliance during food selection. In a series of experimental foraging studies, we examined the relative reliance on vision versus olfaction in three diurnal, primate species with diverse feeding ecologies, including folivorous Coquerel's sifakas (Propithecus coquereli), frugivorous ruffed lemurs (Varecia variegata spp), and generalist ring-tailed lemurs (Lemur catta). We used animals with known color-vision status and foods for which different maturation stages (and hence quality) produce distinct visual and olfactory cues (the latter determined chemically). We first showed that lemurs preferentially selected high-quality foods over low-quality foods when visual and olfactory cues were simultaneously available for both food types. Next, using a novel apparatus in a series of discrimination trials, we either manipulated food quality (while holding sensory cues constant) or manipulated sensory cues (while holding food quality constant). Among our study subjects that showed relatively strong preferences for high-quality foods, folivores required both sensory cues combined to reliably identify their preferred foods, whereas generalists could identify their preferred foods using either cue alone, and frugivores could identify their preferred foods using olfactory, but not visual, cues alone. Moreover, when only high-quality foods were available, folivores and generalists used visual rather than olfactory cues to select food, whereas frugivores used both cue types equally. Lastly, individuals in all three of the study species predominantly relied on sight when choosing between low-quality foods, but species differed in the strength of their sensory biases. Our results generally emphasize visual over olfactory reliance in foraging lemurs, but we suggest that the relative sensory reliance of animals may vary with their feeding ecology. PMID:22870229

Primate Torpor: Regulation of Stress-activated Protein Kinases During Daily Torpor in the Gray Mouse Lemur, Microcebus murinus.

PubMed

Biggar, Kyle K; Wu, Cheng-Wei; Tessier, Shannon N; Zhang, Jing; Pifferi, Fabien; Perret, Martine; Storey, Kenneth B

2015-04-01

Very few selected species of primates are known to be capable of entering torpor. This exciting discovery means that the ability to enter a natural state of dormancy is an ancestral trait among primates and, in phylogenetic terms, is very close to the human lineage. To explore the regulatory mechanisms that underlie primate torpor, we analyzed signal transduction cascades to discover those involved in coordinating tissue responses during torpor. The responses of mitogen-activated protein kinase (MAPK) family members to primate torpor were compared in six organs of control (aroused) versus torpid gray mouse lemurs, Microcebus murinus. The proteins examined include extracellular signal-regulated kinases (ERKs), c-jun NH2-terminal kinases (JNKs), MAPK kinase (MEK), and p38, in addition to stress-related proteins p53 and heat shock protein 27 (HSP27). The activation of specific MAPK signal transduction pathways may provide a mechanism to regulate the expression of torpor-responsive genes or the regulation of selected downstream cellular processes. In response to torpor, each MAPK subfamily responded differently during torpor and each showed organ-specific patterns of response. For example, skeletal muscle displayed elevated relative phosphorylation of ERK1/2 during torpor. Interestingly, adipose tissues showed the highest degree of MAPK activation. Brown adipose tissue displayed an activation of ERK1/2 and p38, whereas white adipose tissue showed activation of ERK1/2, p38, MEK, and JNK during torpor. Importantly, both adipose tissues possess specialized functions that are critical for torpor, with brown adipose required for non-shivering thermogenesis and white adipose utilized as the primary source of lipid fuel for torpor. Overall, these data indicate crucial roles of MAPKs in the regulation of primate organs during torpor. Copyright © 2015. Production and hosting by Elsevier Ltd.

Inferring the Diets of Extinct Giant Lemurs from Osteological Correlates of Muscle Dimensions.

PubMed

Perry, Jonathan M G

2018-02-01

The jaw adductor muscles of extinct mammals are often reconstructed to elucidate paleoecological relationships and to make broad comparisons among taxa. Muscle lever arms, bite load arms, muscle dimensions, and gape are often also reconstructed to better understand feeding. Several different approaches to these and related goals are discussed here. A protocol for reconstructing muscle dimensions and bite force using biomechanically informative skull measurements and osteological proxies of muscle dimensions is described and applied to a case study of subfossil Malagasy lemurs. The results of this case study show that most subfossil lemurs emphasized the masseter and medial pterygoid muscles over the temporalis. This supports the inference that these extinct lemurs depended heavily on tough food like leaves. Exceptions include signals of hard-object feeding in Archaeolemur that vary between A. majori and A. edwardsi. Reconstructions of soft-tissue and function are important for understanding past ecological relationships. Even those based on well-supported osteological proxies from extant analogues have limitations for making precise inferences. Anat Rec, 301:343-362, 2018. © 2018 Wiley Periodicals, Inc. © 2018 Wiley Periodicals, Inc.

DNA from extinct giant lemurs links archaeolemurids to extant indriids

PubMed Central

2008-01-01

Background Although today 15% of living primates are endemic to Madagascar, their diversity was even greater in the recent past since dozens of extinct species have been recovered from Holocene excavation sites. Among them were the so-called "giant lemurs" some of which weighed up to 160 kg. Although extensively studied, the phylogenetic relationships between extinct and extant lemurs are still difficult to decipher, mainly due to morphological specializations that reflect ecology more than phylogeny, resulting in rampant homoplasy. Results Ancient DNA recovered from subfossils recently supported a sister relationship between giant "sloth" lemurs and extant indriids and helped to revise the phylogenetic position of Megaladapis edwardsi among lemuriformes, but several taxa – such as the Archaeolemuridae – still await analysis. We therefore used ancient DNA technology to address the phylogenetic status of the two archaeolemurid genera (Archaeolemur and Hadropithecus). Despite poor DNA preservation conditions in subtropical environments, we managed to recover 94- to 539-bp sequences for two mitochondrial genes among 5 subfossil samples. Conclusion This new sequence information provides evidence for the proximity of Archaeolemur and Hadropithecus to extant indriids, in agreement with earlier assessments of their taxonomic status (Primates, Indrioidea) and in contrast to recent suggestions of a closer relationship to the Lemuridae made on the basis of analyses of dental developmental and postcranial characters. These data provide new insights into the evolution of the locomotor apparatus among lemurids and indriids. PMID:18442367

Nutrient composition of plants consumed by black and white ruffed lemurs, Varecia variegata, in the Betampona Natural Reserve, Madagascar.

PubMed

Schmidt, Debra A; Iambana, R Bernard; Britt, Adam; Junge, Randall E; Welch, Charles R; Porton, Ingrid J; Kerley, Monty S

2010-01-01

The purpose of this study was to quantify the concentrations of crude protein, fat, ash, neutral detergent fiber, acid detergent fiber, lignin, nonstructural carbohydrates, and gross energy in plant foods consumed by wild black and white ruffed lemurs (Varecia variegata). Calcium, phosphorous, magnesium, potassium, sodium, iron, zinc, copper, manganese, molybdenum, and selenium concentrations were also determined. A total of 122 samples from 33 plant families and more than 60 species were collected and analyzed for their nutritional content. The specific nutrient needs of black and white ruffed lemurs are unknown, but quantifying the nutritional composition of the foods they consume in the wild will help nutritionists and veterinarians formulate more appropriate diets for captive ruffed lemurs. This information will also supply information on how man-induced habitat changes affect the nutritional composition of foods consumed by free-ranging lemurs. (c) 2009 Wiley-Liss, Inc.

Nutrition and behavior of lemurs.

PubMed

Junge, Randall E; Williams, Cathy V; Campbell, Jennifer

2009-05-01

Attention to nutritional and behavioral factors is important for appropriate care of lemurs in captivity. Although only a few species are commonly held in captivity, differences between them are important. Knowledge of feeding ecology and natural diet guide nutrition guidelines, as well as management and prevention of common nutrition-related disorders, including obesity, diabetes, and iron-storage disease. Behavioral characteristics that influence captive management are related to social organization, reproductive behavior, territoriality, and infant care. Housing animals in appropriate social groupings in adequately complex environments reduces abnormal behaviors, and addition of enrichment activities and operant conditioning encourages normal behaviors.

Relaxed open mouth as a playful signal in wild ring-tailed lemurs.

PubMed

Palagi, Elisabetta; Norscia, Ivan; Spada, Giulia

2014-11-01

Play signals are commonly used by animals to communicate their playful motivation and to limit the risk that rough acts are misunderstood by playmates. The relaxed open mouth is the most common facial expression performed during play in many mammals and represents the ritualized version of the movement anticipating a play bite. The signaling nature of this expression has been proven in many haplorrhine species but never demonstrated in strepsirrhines. Our purpose was assessing whether, also in strepsirrhines, the relaxed open mouth has an actual communicative function. We studied wild ring-tailed lemurs (Lemur catta), characterized by highly social habits including intense playful interactions. They largely use playful signals, mostly performed with the black and white tail. The signaling function of the tail (tail play) has been widely demonstrated. We analyzed both tail play and the relaxed open mouth to verify how their distribution is affected by different play variables (e.g., play session symmetry, number of play mates, previous use of the same pattern). Indeed, ring-tailed lemurs use the relaxed open mouth as a communicative signal during play. Relaxed open mouth was more frequent during unbalanced interactions showing the highest asymmetry in the patterns performed by the two players (offensive/neutral). Compared to tail play, relaxed open mouth was more frequent during dyadic than polyadic interactions and, as a highly directional signal, it was more frequently replicated by the play mate. Therefore, the relaxed open mouth needs to be performed face-to-face so that signal detection can be optimized. Similar to previous findings in monkeys and apes, the relaxed open mouth in lemurs seems to be a ritualized signal used to engage and, perhaps, sustain playful interaction. © 2014 Wiley Periodicals, Inc.

Two New Species of Sucking Lice (Phthiraptera: Anoplura: Polyplacidae) From Endangered, Hibernating Lemurs (Primates: Cheirogaleidae).

PubMed

Durden, Lance A; Blanco, Marina B; Seabolt, Matthew H

2017-05-01

Lemurpediculus robbinsi sp. nov. is described from Crossley's dwarf lemur, Cheirogaleus crossleyi A. Grandidier, and Lemurpediculus claytoni sp. nov. is described from Sibree's dwarf lemur, Cheirogaleus sibreei Forsyth Major, from Madagascar. Both sexes of each new louse species are illustrated and distinguished from the two previously known species of Lemurpediculus: L. verruculosus (Ward) and L. petterorum Paulian. With the addition of two new species to the genus, an amended description of Lemurpediculus is provided. The two hosts of the new louse species are morphologically similar, endangered, obligately hibernating lemurs. These two species of lemurs are sometimes sympatric in rainforests in eastern Madagascar. Despite the morphological similarity of the two host species, their lice are morphologically distinct and are easiest to identify based on the shape of the subgenital plate of the female and the shape of the genitalia in the male. Both new species of lice should be considered to be endangered because their hosts are endangered. It is not known if either of the new species of lice are vectors of pathogens or parasites to their hosts. © The Authors 2017. Published by Oxford University Press on behalf of Entomological Society of America. All rights reserved. For Permissions, please email: journals.permissions@oup.com Version of Record, first published online February 15, 2017 with fixed content and layout in compliance with Art. 8.1.3.2 ICZN.

Aging Research Using Mouse Models

PubMed Central

Ackert-Bicknell, Cheryl L.; Anderson, Laura; Sheehan, Susan; Hill, Warren G.; Chang, Bo; Churchill, Gary A.; Chesler, Elissa J.; Korstanje, Ron; Peters, Luanne L.

2015-01-01

Despite the dramatic increase in human lifespan over the past century, there remains pronounced variability in “health-span”, or the period of time in which one is generally healthy and free of disease. Much of the variability in health-span and lifespan is thought to be genetic in origin. Understanding the genetic mechanisms of aging and identifying ways to boost longevity is a primary goal in aging research. Here, we describe a pipeline of phenotypic assays for assessing mouse models of aging. This pipeline includes behavior/cognition testing, body composition analysis, and tests of kidney function, hematopoiesis, immune function and physical parameters. We also describe study design methods for assessing lifespan and health-span, and other important considerations when conducting aging research in the laboratory mouse. The tools and assays provided can assist researchers with understanding the correlative relationships between age-associated phenotypes and, ultimately, the role of specific genes in the aging process. PMID:26069080

Development and application of a phylogenomic toolkit: Resolving the evolutionary history of Madagascar’s lemurs

PubMed Central

Horvath, Julie E.; Weisrock, David W.; Embry, Stephanie L.; Fiorentino, Isabella; Balhoff, James P.; Kappeler, Peter; Wray, Gregory A.; Willard, Huntington F.; Yoder, Anne D.

2008-01-01

Lemurs and the other strepsirrhine primates are of great interest to the primate genomics community due to their phylogenetic placement as the sister lineage to all other primates. Previous attempts to resolve the phylogeny of lemurs employed limited mitochondrial or small nuclear data sets, with many relationships poorly supported or entirely unresolved. We used genomic resources to develop 11 novel markers from nine chromosomes, representing ∼9 kb of nuclear sequence data. In combination with previously published nuclear and mitochondrial loci, this yields a data set of more than 16 kb and adds ∼275 kb of DNA sequence to current databases. Our phylogenetic analyses confirm hypotheses of lemuriform monophyly and provide robust resolution of the phylogenetic relationships among the five lemuriform families. We verify that the genus Daubentonia is the sister lineage to all other lemurs. The Cheirogaleidae and Lepilemuridae are sister taxa and together form the sister lineage to the Indriidae; this clade is the sister lineage to the Lemuridae. Divergence time estimates indicate that lemurs are an ancient group, with their initial diversification occurring around the Cretaceous-Tertiary boundary. Given the power of this data set to resolve branches in a notoriously problematic area of primate phylogeny, we anticipate that our phylogenomic toolkit will be of value to other studies of primate phylogeny and diversification. Moreover, the methods applied will be broadly applicable to other taxonomic groups where phylogenetic relationships have been notoriously difficult to resolve. PMID:18245770

Multi-tissue DNA methylation age predictor in mouse.

PubMed

Stubbs, Thomas M; Bonder, Marc Jan; Stark, Anne-Katrien; Krueger, Felix; von Meyenn, Ferdinand; Stegle, Oliver; Reik, Wolf

2017-04-11

DNA methylation changes at a discrete set of sites in the human genome are predictive of chronological and biological age. However, it is not known whether these changes are causative or a consequence of an underlying ageing process. It has also not been shown whether this epigenetic clock is unique to humans or conserved in the more experimentally tractable mouse. We have generated a comprehensive set of genome-scale base-resolution methylation maps from multiple mouse tissues spanning a wide range of ages. Many CpG sites show significant tissue-independent correlations with age which allowed us to develop a multi-tissue predictor of age in the mouse. Our model, which estimates age based on DNA methylation at 329 unique CpG sites, has a median absolute error of 3.33 weeks and has similar properties to the recently described human epigenetic clock. Using publicly available datasets, we find that the mouse clock is accurate enough to measure effects on biological age, including in the context of interventions. While females and males show no significant differences in predicted DNA methylation age, ovariectomy results in significant age acceleration in females. Furthermore, we identify significant differences in age-acceleration dependent on the lipid content of the diet. Here we identify and characterise an epigenetic predictor of age in mice, the mouse epigenetic clock. This clock will be instrumental for understanding the biology of ageing and will allow modulation of its ticking rate and resetting the clock in vivo to study the impact on biological age.

Biomedical evaluation of free-ranging red ruffed lemurs (Varecia rubra) within the Masoala National Park, Madagascar.

PubMed

Dutton, Christopher J; Junge, Randall E; Louis, Edward E

2008-03-01

Complete health assessments were performed on 22 adult red ruffed lemurs (Varecia rubra), comprising nine males and 13 females, found within the Masoala National Park in northeast Madagascar. Each animal was anesthetized using tiletamine and zolazepam and underwent a thorough physical examination, including measurement of its weight and vital signs; blood collection for hematology, plasma total protein concentration, serum chemistries, fat-soluble vitamins, trace minerals, assessment of iron metabolism, toxoplasmosis serology, viral serologies, and examination for hemoparasites; fecal collection for bacterial culture and parasite examination; and collection of a representative number of any ectoparasites. Comparison of blood values with those of captive lemurs demonstrated a number of significant differences thought to be associated with physiologic state (e.g., reproductive stage and stress), hydration, and diet. There was no evidence of serious infectious diseases, and hemoparasites were not detected. The enteric flora appeared unremarkable; however, results may have been skewed toward more cold-tolerant bacteria. The fecal parasite burden was low. Lemurostrongylus spp. was identified in two of the lemurs, and there were moderate numbers of Laelapidae mites present on approximately one third of the lemurs. This study demonstrated the substantial amount of data that can be collected from free-ranging populations, considered invaluable in the management of captive populations, in reducing the incidence of captivity-related diseases, and in the risk assessment associated with reintroduction programs.

Lemur responses to edge effects in the Vohibola III classified forest, Madagascar.

PubMed

Lehman, Shawn M; Rajaonson, Andry; Day, Sabine

2006-03-01

Forest edges are dynamic zones characterized by the penetration (to varying depths and intensities) of conditions from the surrounding environment (matrix) into the forest interior. Although edge effects influence many tropical organisms, they have not been studied directly in primates. Edge effects are particularly relevant to lemurs because of the highly fragmented forest landscapes found in Madagascar. In this study, data are presented regarding how the densities of six lemur species (Avahi laniger, Cheirogaleus major, Eulemur rubriventer, Hapalemur griseus griseus, Microcebus rufus, and Propithecus diadema edwardsi) varied between six 500-m interior transects and six 500-m edge transects in the Vohibola III Classified Forest in SE Madagascar. Diurnal (n = 433) and nocturnal (n = 128) lemur surveys were conducted during June-October 2003 and May-November 2004. A. laniger, E. rubriventer, and H. g. griseus exhibited a neutral edge response (no differences in densities between habitats). M. rufus and P. d. edwardsi had a positive edge response (higher densities in edge habitats), which may be related to edge-related variations in food abundance and quality. Positive edge responses by M. rufus and P. d. edwardsi may ultimately be detrimental due to edge-related anthropogenic factors (e.g., hunting by local people). The negative edge response exhibited by C. major (lower densities in edge habitats) may result from heightened ambient temperatures that inhibit torpor in edge habitats.

Phylogeny and Divergence Times of Lemurs Inferred with Recent and Ancient Fossils in the Tree.

PubMed

Herrera, James P; Dávalos, Liliana M

2016-09-01

Paleontological and neontological systematics seek to answer evolutionary questions with different data sets. Phylogenies inferred for combined extant and extinct taxa provide novel insights into the evolutionary history of life. Primates have an extensive, diverse fossil record and molecular data for living and extinct taxa are rapidly becoming available. We used two models to infer the phylogeny and divergence times for living and fossil primates, the tip-dating (TD) and fossilized birth-death process (FBD). We collected new morphological data, especially on the living and extinct endemic lemurs of Madagascar. We combined the morphological data with published DNA sequences to infer near-complete (88% of lemurs) time-calibrated phylogenies. The results suggest that primates originated around the Cretaceous-Tertiary boundary, slightly earlier than indicated by the fossil record and later than previously inferred from molecular data alone. We infer novel relationships among extinct lemurs, and strong support for relationships that were previously unresolved. Dates inferred with TD were significantly older than those inferred with FBD, most likely related to an assumption of a uniform branching process in the TD compared with a birth-death process assumed in the FBD. This is the first study to combine morphological and DNA sequence data from extinct and extant primates to infer evolutionary relationships and divergence times, and our results shed new light on the tempo of lemur evolution and the efficacy of combined phylogenetic analyses. © The Author(s) 2016. Published by Oxford University Press, on behalf of the Society of Systematic Biologists. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

The influence of visitor interaction on the behavior of captive crowned lemurs (Eulemur coronatus) and implications for welfare.

PubMed

Jones, H; McGregor, P K; Farmer, H L A; Baker, K R

2016-05-01

Research suggests that zoo visitors can have positive, negative, and neutral impacts on captive primate welfare; however, research investigating the implications of visitor-animal feeding experiences is extremely limited. In the UK, a large proportion of BIAZA zoos that house lemur species offer visitor interaction experiences (16 out of 33). This study investigated the impact on the behavior of a family group of crowned lemurs (Eulemur coronatus) housed at Newquay Zoo, UK of visitors, accompanied by a keeper, entering the enclosure to feed the lemurs. Behavior was observed under four conditions: (i) during visitor feed; (ii) 30 min post-visitor feed; (iii) during a keeper feed; and (iv) 30 min post-keeper feed. Keeper feeds were conducted by keepers only, on the day after visitor feeds. The lemur group spent significantly less time performing aggressive behavior and was also significantly more interactive with keepers during visitor feeds compared with keeper-only feeds. There was no significant difference in behaviors performed immediately after interacting with visitors. Over the study period, there was a tendency for interactions with visitors to increase, and for interactions with keepers during visitor feeds to decrease. After a 28-day interval without visitor interaction, the lemurs' interaction with visitors had returned to the level recorded at the start of the study. In conclusion, visitor interaction did not compromise the welfare of the study subjects in either the short- or long-term, while an increase in visitor interactions over time has interesting implications for the enrichment properties of, or habituation to, unfamiliar humans. Zoo Biol. 35:222-227, 2016. © 2016 Wiley Periodicals, Inc. © 2016 Wiley Periodicals, Inc.

The mouse age phenome knowledgebase and disease-specific inter-species age mapping.

PubMed

Geifman, Nophar; Rubin, Eitan

2013-01-01

Similarities between mice and humans lead to generation of many mouse models of human disease. However, differences between the species often result in mice being unreliable as preclinical models for human disease. One difference that might play a role in lowering the predictivity of mice models to human diseases is age. Despite the important role age plays in medicine, it is too often considered only casually when considering mouse models. We developed the mouse-Age Phenotype Knowledgebase, which holds knowledge about age-related phenotypic patterns in mice. The knowledgebase was extensively populated with literature-derived data using text mining techniques. We then mapped between ages in humans and mice by comparing the age distribution pattern for 887 diseases in both species. The knowledgebase was populated with over 9800 instances generated by a text-mining pipeline. The quality of the data was manually evaluated, and was found to be of high accuracy (estimated precision >86%). Furthermore, grouping together diseases that share similar age patterns in mice resulted in clusters that mirror actual biomedical knowledge. Using these data, we matched age distribution patterns in mice and in humans, allowing for age differences by shifting either of the patterns. High correlation (r(2)>0.5) was found for 223 diseases. The results clearly indicate a difference in the age mapping between different diseases: age 30 years in human is mapped to 120 days in mice for Leukemia, but to 295 days for Anemia. Based on these results we generated a mice-to-human age map which is publicly available. We present here the development of the mouse-APK, its population with literature-derived data and its use to map ages in mice and human for 223 diseases. These results present a further step made to bridging the gap between humans and mice in biomedical research.

Lemur behaviour informs the evolution of social monogamy.

PubMed

Kappeler, Peter M

2014-11-01

Recent comparative analyses reached contradictory conclusions about the evolutionary origins of social monogamy in primates and other mammals, but they ignored variation in social bond quality between pair-partners. Recent field studies of Malagasy primates (lemurs) with variable intersexual bonds indicate independent evolutionary transitions to pair-living from solitary and group-living ancestors, respectively, as well as four cumulative steps in evolutionary transitions from a solitary life style to pair-living that resolve some contradictory results of previous studies. Copyright © 2014 Elsevier Ltd. All rights reserved.

Evidence that displacement activities facilitate behavioural transitions in ring-tailed lemurs.

PubMed

Buckley, Victoria; Semple, Stuart

2012-07-01

Displacement activities are behavioural patterns defined by their apparent irrelevance to an animal's ongoing actions. Despite being identified in diverse taxa, their function remains poorly understood. One hypothesis posits that displacement activities facilitate transitions between different behaviours by mediating changes in animals' motivational state. Under this hypothesis, it is predicted that displacement activities will occur more frequently around changes in behaviour than at other times, and also that rates of displacement activities will be higher before than after such behavioural transitions. We tested these two predictions in wild ring-tailed lemurs (Lemur catta). During focal observations, animals' behavioural state was continuously recorded, as were all occurrences of self-scratching, a common displacement activity in this species. Self-scratching rates were found to be significantly elevated both before and after behavioural transitions. Furthermore, self-scratching rates were significantly higher before behavioural transitions occurred than after. These results, therefore, provide support for the hypothesis that displacement activities facilitate behavioural transitions in L. catta. Copyright © 2012 Elsevier B.V. All rights reserved.

Survey of minerals and fat-soluble vitamins in captive black and white ruffed lemurs (Varecia variegata).

PubMed

Crawford, Graham C; Puschner, Birgit; Dierenfeld, Ellen S; Dunker, Freeland

2009-12-01

Serum and whole blood samples from 64 clinically normal captive black and white ruffed lemurs (Varecia variegata), aged 6 mo to 32 yr, were analyzed to survey mineral and fat-soluble vitamin concentrations. All animals were fed a commercial primate food and a wide range of fruits and vegetables. Specific commercial diet information was available for 52 animals that were fed one of 10 different diets. Data analysis showed no differences in the analytes attributable to sex or access to natural ultraviolet light. Serum phosphorus (range: 1.4-3.1 mmol/L) was significantly higher and retinol (range: 0.38-1.23 micromol/L) was significantly lower in young animals (< or =4 yr). Iron (range: 17.2-77.0 micromol/L) and copper (range: 10.7-53.3 micromol/L) were much higher than concentrations reported in other free-ranging lemur species, and in some animals were at levels considered potentially toxic in domestic animals. Magnesium (range: 0.66-2.04 mmol/L), sodium (range: 111-201 mmol/L), and potassium (range: 2.0-6.8 mmol/L) ranged both lower and higher than concentrations considered adequate for a mammal, but were similar to concentrations reported in wild red ruffed lemurs (Varecia rubra), a closely related species. Selenium (range: 3.5-7.7 micromol/L) was within the range expected for a mammal, but higher than concentrations reported in wild V rubra. Zinc (range: 9.2-62.7 micromol/L) was similar to concentrations reported in V. rubra. Calcidiol (range: <12.5-144.8 nmol/L) and retinol (range: 0.38-2.95 micromol/L) were both lower and higher than concentrations reported in V. rubra. Lower serum calcidiol concentration correlated with lower commercial dietary vitamin D3. Alpha-tocopherol (range: 1.2-17.6 micromol/L) and y-tocopherol (range: 0.3-3.9 micromol/L) were within a range expected in a captive frugivorous primate but higher than concentrations found in wild V. rubra.

Can black-and-white ruffed lemurs (Varecia variegata) solve object permanence tasks?

PubMed

Mallavarapu, Suma; Perdue, Bonnie M; Stoinski, Tara S; Maple, Terry L

2013-04-01

We examined object permanence in black-and-white-ruffed lemurs (Varecia variegata) at Zoo Atlanta. A series of visible and invisible displacement tasks with suitable controls were presented to five adult subjects. Subjects performed significantly above chance on all regular tasks, except for the double invisible displacements. Subjects failed visible and invisible controls. Failure on the control trials did not appear to be because subjects used the "last box touched" strategy (subjects did not choose the last box touched significantly more than expected by chance). However, a substantial percentage of choices was made to the last box touched by the experimenter. There was no significant difference between this percentage, and the percentage of choices made to the baited box (on both visible and invisible controls), which indicates that subjects were drawn to both boxes which the experimenter visited/touched, and thus failed the controls. Based on the results from the present study, we believe that there is no evidence that black-and-white ruffed lemurs understand visible and invisible tasks in the traditional object permanence battery. © 2013 Wiley Periodicals, Inc.

Stable isotopes document resource partitioning and effects of forest disturbance on sympatric cheirogaleid lemurs

NASA Astrophysics Data System (ADS)

Crowley, B. E.; Blanco, M. B.; Arrigo-Nelson, S. J.; Irwin, M. T.

2013-10-01

The future of Madagascar’s forests and their resident lemurs is precarious. Determining how species respond to forest fragmentation is essential for management efforts. We use stable isotope biogeochemistry to investigate how disturbance affects resource partitioning between two genera of cheirogaleid lemurs ( Cheirogaleus and Microcebus) from three humid forest sites: continuous and fragmented forest at Tsinjoarivo, and selectively logged forest at Ranomafana. We test three hypotheses: (H1) cheirogaleids are unaffected by forest fragmentation, (H2) species respond individually to disturbance and may exploit novel resources in fragmented habitat, and (H3) species alter their behavior to rely on the same key resource in disturbed forest. We find significant isotopic differences among species and localities. Carbon data suggest that Microcebus feed lower in the canopy than Cheirogaleus at all three localities and that sympatric Cheirogaleus crossleyi and C. sibreei feed at different canopy heights in the fragmented forest. Microcbus have higher nitrogen isotope values than Cheirogaleus at all localities, indicating more faunivory. After accounting for baseline isotope values in plants, our results provide the most support for H3. We find similar isotopic variations among localities for both genera. Small differences in carbon among localities may reflect shifts in diet or habitat use. Elevated nitrogen values for cheirogaleid lemurs in fragments may reflect increased arthropod consumption or nutritional stress. These results suggest that cheirogaleids are affected by forest disturbance in Eastern Madagascar and stress the importance of accounting for baseline isotopic differences in plants in any work comparing localities.

Acoustic divergence in the communication of cryptic species of nocturnal primates (Microcebus ssp.)

PubMed Central

Braune, Pia; Schmidt, Sabine; Zimmermann, Elke

2008-01-01

Background A central question in evolutionary biology is how cryptic species maintain species cohesiveness in an area of sympatry. The coexistence of sympatrically living cryptic species requires the evolution of species-specific signalling and recognition systems. In nocturnal, dispersed living species, specific vocalisations have been suggested to act as an ideal premating isolation mechanism. We studied the structure and perception of male advertisement calls of three nocturnal, dispersed living mouse lemur species, the grey mouse lemur (Microcebus murinus), the golden brown mouse lemur (M. ravelobensis) and the Goodman's mouse lemur (M. lehilahytsara). The first two species occur sympatrically, the latter lives allopatrically to them. Results A multi-parameter sound analysis revealed prominent differences in the frequency contour and in the duration of advertisement calls. To test whether mouse lemurs respond specifically to calls of the different species, we conducted a playback experiment with M. murinus from the field using advertisement calls and alarm whistle calls of all three species. Individuals responded significantly stronger to conspecific than to heterospecific advertisement calls but there were no differences in response behaviour towards statistically similar whistle calls of the three species. Furthermore, sympatric calls evoked weaker interest than allopatric advertisement calls. Conclusion Our results provide the first evidence for a specific relevance of social calls for speciation in cryptic primates. They furthermore support that specific differences in signalling and recognition systems represent an efficient premating isolation mechanism contributing to species cohesiveness in sympatrically living species. PMID:18462484

Smelling wrong: hormonal contraception in lemurs alters critical female odour cues

PubMed Central

Crawford, Jeremy Chase; Boulet, Marylène; Drea, Christine M.

2011-01-01

Animals, including humans, use olfaction to assess potential social and sexual partners. Although hormones modulate olfactory cues, we know little about whether contraception affects semiochemical signals and, ultimately, mate choice. We examined the effects of a common contraceptive, medroxyprogesterone acetate (MPA), on the olfactory cues of female ring-tailed lemurs (Lemur catta), and the behavioural response these cues generated in male conspecifics. The genital odorants of contracepted females were dramatically altered, falling well outside the range of normal female variation: MPA decreased the richness and modified the relative abundances of volatile chemicals expressed in labial secretions. Comparisons between treatment groups revealed several indicator compounds that could reliably signal female reproductive status to conspecifics. MPA also changed a female's individual chemical ‘signature’, while minimizing her chemical distinctiveness relative to other contracepted females. Most remarkably, MPA degraded the chemical patterns that encode honest information about genetic constitution, including individual diversity (heterozygosity) and pairwise relatedness to conspecifics. Lastly, males preferentially investigated the odorants of intact over contracepted females, clearly distinguishing those with immediate reproductive potential. By altering the olfactory cues that signal fertility, individuality, genetic quality and relatedness, contraceptives may disrupt intraspecific interactions in primates, including those relevant to kin recognition and mate choice. PMID:20667870

Wild-derived mouse stocks: an underappreciated tool for aging research

PubMed Central

2008-01-01

Virtually all biomedical research makes use of a relatively small pool of laboratory-adapted, inbred, isogenic stocks of mice. Although the advantages of these models are many, there are a number of disadvantages as well. When studying a multifaceted process such as aging, the problems associated with using laboratory stocks are greatly inflated. On the other hand, wild-derived mouse stocks, loosely defined here as either wild-caught individuals or the recent progeny of wild-caught individuals, have much to offer to biogerontology research. Hence, the aims of this review are threefold: (1) to (re)acquaint readers with the pros and cons of using a typical inbred laboratory mouse model for aging research; (2) to reintroduce the notion of using wild-derived mouse stocks in aging research as championed by Austad, Miller and others for more than a decade, and (3) to provide an overview of recent advances in biogerontology using wild-derived mouse stocks. PMID:19424863

The Use of an Invasive Species Habitat by a Small Folivorous Primate: Implications for Lemur Conservation in Madagascar.

PubMed

Eppley, Timothy M; Donati, Giuseppe; Ramanamanjato, Jean-Baptiste; Randriatafika, Faly; Andriamandimbiarisoa, Laza N; Rabehevitra, David; Ravelomanantsoa, Robertin; Ganzhorn, Jörg U

2015-01-01

The lemurs of Madagascar are among the most threatened mammalian taxa in the world, with habitat loss due to shifting cultivation and timber harvest heavily contributing to their precarious state. Deforestation often leads to fragmentation, resulting in mixed-habitat matrices throughout a landscape where disturbed areas are prone to invasion by exotic plants. Our study site, the Mandena littoral forest (southeast Madagascar), is a matrix of littoral forest, littoral swamp, and Melaleuca swamp habitats. Here, Melaleuca quinquenervia has invaded the wetland ecosystem, creating a mono-dominant habitat that currently provides the only potential habitat corridor between forest fragments. We sought to understand the role of this invasive Melaleuca swamp on the behavioral ecology of a threatened, small-bodied folivore, the southern bamboo lemur (Hapalemur meridionalis). We collected botanical and behavioral data on four groups of H. meridionalis between January and December 2013. Our results confirm Melaleuca swamp as an important part of their home range: while lemurs seasonally limited activities to certain habitats, all groups were capable of utilizing this invasive habitat for feeding and resting. Furthermore, the fact that Hapalemur use an invasive plant species as a dispersal corridor increases our knowledge of their ecological flexibility, and may be useful in the conservation management of remaining threatened populations.

The Use of an Invasive Species Habitat by a Small Folivorous Primate: Implications for Lemur Conservation in Madagascar

PubMed Central

Eppley, Timothy M.; Donati, Giuseppe; Ramanamanjato, Jean-Baptiste; Randriatafika, Faly; Andriamandimbiarisoa, Laza N.; Rabehevitra, David; Ravelomanantsoa, Robertin; Ganzhorn, Jörg U.

2015-01-01

The lemurs of Madagascar are among the most threatened mammalian taxa in the world, with habitat loss due to shifting cultivation and timber harvest heavily contributing to their precarious state. Deforestation often leads to fragmentation, resulting in mixed-habitat matrices throughout a landscape where disturbed areas are prone to invasion by exotic plants. Our study site, the Mandena littoral forest (southeast Madagascar), is a matrix of littoral forest, littoral swamp, and Melaleuca swamp habitats. Here, Melaleuca quinquenervia has invaded the wetland ecosystem, creating a mono-dominant habitat that currently provides the only potential habitat corridor between forest fragments. We sought to understand the role of this invasive Melaleuca swamp on the behavioral ecology of a threatened, small-bodied folivore, the southern bamboo lemur (Hapalemur meridionalis). We collected botanical and behavioral data on four groups of H. meridionalis between January and December 2013. Our results confirm Melaleuca swamp as an important part of their home range: while lemurs seasonally limited activities to certain habitats, all groups were capable of utilizing this invasive habitat for feeding and resting. Furthermore, the fact that Hapalemur use an invasive plant species as a dispersal corridor increases our knowledge of their ecological flexibility, and may be useful in the conservation management of remaining threatened populations. PMID:26536667

Relatedness communicated in lemur scent

NASA Astrophysics Data System (ADS)

Morelli, Toni Lyn; Hayes, R. Andrew; Nahrung, Helen F.; Goodwin, Thomas E.; Harelimana, Innocent H.; MacDonald, Laura J.; Wright, Patricia C.

2013-08-01

Lemurs are the most olfactory-oriented of primates, yet there is still only a basic level of understanding of what their scent marks communicate. We analyzed scent secretions from Milne-Edwards' sifakas ( Propithecus edwardsi) collected in their natural habitat of Ranomafana National Park, Madagascar. We sought to test whether the scent mark could signal genetic relatedness in addition to species, sex, season, and individuality. We not only found correlations ( r 2 = 0.38, P = 0.017) between the total olfactory fingerprint and genetic relatedness but also between relatedness and specific components of the odor, despite the complex environmental signals from differences in diet and behavior in a natural setting. To the best of our knowledge, this is the first demonstration of an association between genetic relatedness and chemical communication in a wild primate population. Furthermore, we found a variety of compounds that were specific to each sex and each sampling period. This research shows that scent marks could act as a remote signal to avoid inbreeding, optimize mating opportunities, and potentially aid kin selection.

Innovation and behavioral flexibility in wild redfronted lemurs (Eulemur rufifrons).

PubMed

Huebner, Franziska; Fichtel, Claudia

2015-05-01

Innovations and problem-solving abilities can provide animals with important ecological advantages as they allow individuals to deal with novel social and ecological challenges. Innovation is a solution to a novel problem or a novel solution to an old problem, with the latter being especially difficult. Finding a new solution to an old problem requires individuals to inhibit previously applied solutions to invent new strategies and to behave flexibly. We examined the role of experience on cognitive flexibility to innovate and to find new problem-solving solutions with an artificial feeding task in wild redfronted lemurs (Eulemur rufifrons). Four groups of lemurs were tested with feeding boxes, each offering three different techniques to extract food, with only one technique being available at a time. After the subjects learned a technique, this solution was no longer successful and subjects had to invent a new technique. For the first transition between task 1 and 2, subjects had to rely on their experience of the previous technique to solve task 2. For the second transition, subjects had to inhibit the previously learned technique to learn the new task 3. Tasks 1 and 2 were solved by most subjects, whereas task 3 was solved by only a few subjects. In this task, besides behavioral flexibility, especially persistence, i.e., constant trying, was important for individual success during innovation. Thus, wild strepsirrhine primates are able to innovate flexibly, suggesting a general ecological relevance of behavioral flexibility and persistence during innovation and problem solving across all primates.

Is wounding aggression in zoo-housed chimpanzees and ring-tailed lemurs related to zoo visitor numbers?

PubMed

Hosey, Geoff; Melfi, Vicky; Formella, Isabel; Ward, Samantha J; Tokarski, Marina; Brunger, Dave; Brice, Sara; Hill, Sonya P

2016-05-01

Chimpanzees in laboratory colonies experience more wounds on weekdays than on weekends, which has been attributed to the increased number of people present during the week; thus, the presence of more people was interpreted as stressful. If this were also true for primates in zoos, where high human presence is a regular feature, this would clearly be of concern. Here we examine wounding rates in two primate species (chimpanzees Pan troglodytes and ring-tailed lemurs Lemur catta) at three different zoos, to determine whether they correlate with mean number of visitors to the zoo. Wounding data were obtained from a zoo electronic record keeping system (ZIMS™). The pattern of wounds did not correlate with mean gate numbers for those days for either species in any group. We conclude that there is no evidence that high visitor numbers result in increased woundings in these two species when housed in zoos. Zoo Biol. 35:205-209, 2016. © 2016 Wiley Periodicals, Inc. © 2016 Wiley Periodicals, Inc.

Comparison of biomedical evaluation for white-fronted brown lemurs (Eulemur fulvus albifrons) from four sites in Madagascar.

PubMed

Junge, Randall E; Dutton, Christopher J; Knightly, Felicia; Williams, Cathy V; Rasambainarivo, Fidisoa T; Louis, Edward E

2008-12-01

Health and nutritional assessments of wildlife are important management tools and can provide a means to evaluate ecosystem health. Such examinations were performed on 37 white-fronted brown lemurs (Eulemur fulvus albifrons) from four sites in Madagascar. Comparison of health parameters between sites revealed statistically significant differences in body weight, body temperature, respiratory rate, hematology parameters (white cell count, hematocrit, segmented neutrophil count, and lymphocyte count), serum chemistry parameters (aspartate aminotransferase, alanine aminotransferase, serum alkaline phosphatase, total protein, albumin, phosphorus, calcium, sodium, chloride, and creatinine phosphokinase), and nutrition parameters (copper, zinc, ferritin, retinol, tocopherol, and 25-hydroxycholecalciferol). Two of 10 lemurs tested were positive for toxoplasmosis; none of 10 were positive for Cryptosporidium or Giardia. Enteric bacteria and endo- and ectoparasites were typical. Statistically different values in hematology and chemistry values probably do not reflect clinically significant differences, whereas nutrition parameter differences are likely related to season, soil, and forage availability.

Mapping the social network: tracking lice in a wild primate (Microcebus rufus) population to infer social contacts and vector potential

PubMed Central

2012-01-01

Background Studies of host-parasite interactions have the potential to provide insights into the ecology of both organisms involved. We monitored the movement of sucking lice (Lemurpediculus verruculosus), parasites that require direct host-host contact to be transferred, in their host population of wild mouse lemurs (Microcebus rufus). These lemurs live in the rainforests of Madagascar, are small (40 g), arboreal, nocturnal, solitary foraging primates for which data on population-wide interactions are difficult to obtain. We developed a simple, cost effective method exploiting the intimate relationship between louse and lemur, whereby individual lice were marked, without removal from their host, with an individualized code, and tracked throughout the lemur population. We then tested the hypotheses that 1) the frequency of louse transfers, and thus interactions, would decrease with increasing distance between paired individual lemurs; 2) due to host polygynandry, social interactions and hence louse transfers would increase during the onset of the breeding season; and 3) individual mouse lemurs would vary in their contributions to the spread of lice. Results We show that louse transfers involved 43.75% of the studied lemur population, exclusively males. Louse transfers peaked during the breeding season, perhaps due to increased social interactions between lemurs. Although trap-based individual lemur ranging patterns are restricted, louse transfer rate does not correlate with the distance between lemur trapping locales, indicating wider host ranging behavior and a greater risk of rapid population-wide pathogen transmission than predicted by standard trapping data alone. Furthermore, relatively few lemur individuals contributed disproportionately to the rapid spread of lice throughout the population. Conclusions Using a simple method, we were able to visualize exchanges of lice in a population of cryptic wild primates. This method not only provided insight into the

Genetic mouse models of brain ageing and Alzheimer's disease.

PubMed

Bilkei-Gorzo, Andras

2014-05-01

Progression of brain ageing is influenced by a complex interaction of genetic and environmental factors. Analysis of genetically modified animals with uniform genetic backgrounds in a standardised, controlled environment enables the dissection of critical determinants of brain ageing on a molecular level. Human and animal studies suggest that increased load of damaged macromolecules, efficacy of DNA maintenance, mitochondrial activity, and cellular stress defences are critical determinants of brain ageing. Surprisingly, mouse lines with genetic impairment of anti-oxidative capacity generally did not show enhanced cognitive ageing but rather an increased sensitivity to oxidative challenge. Mouse lines with impaired mitochondrial activity had critically short life spans or severe and rapidly progressing neurodegeneration. Strains with impaired clearance in damaged macromolecules or defects in the regulation of cellular stress defences showed alterations in the onset and progression of cognitive decline. Importantly, reduced insulin/insulin-like growth factor signalling generally increased life span but impaired cognitive functions revealing a complex interaction between ageing of the brain and of the body. Brain ageing is accompanied by an increased risk of developing Alzheimer's disease. Transgenic mouse models expressing high levels of mutant human amyloid precursor protein showed a number of symptoms and pathophysiological processes typical for early phase of Alzheimer's disease. Generally, therapeutic strategies effective against Alzheimer's disease in humans were also active in the Tg2576, APP23, APP/PS1 and 5xFAD lines, but a large number of false positive findings were also reported. The 3xtg AD model likely has the highest face and construct validity but further studies are needed. Copyright © 2013 Elsevier Inc. All rights reserved.

Age-related changes in mouse bone permeability.

PubMed

Rodriguez-Florez, Naiara; Oyen, Michelle L; Shefelbine, Sandra J

2014-03-21

The determination of lacunar-canalicular permeability is essential for understanding local fluid flow in bone, which may indicate how bone senses changes in the mechanical environment to regulate mechano-adaptation. The estimates of lacunar-canalicular permeability found in the literature vary by up to eight orders of magnitude, and age-related permeability changes have not been measured in non-osteonal mouse bone. The objective of this study is to use a poroelastic approach based on nanoindentation data to characterize lacunar-canalicular permeability in murine bone as a function of age. Nine wild type C57BL/6 mice of different ages (2, 7 and 12 months) were used. Three tibiae from each age group were embedded in epoxy resin, cut in half and indented in the longitudinal direction in the mid-cortex using two spherical fluid indenter tips (R=238 μm and 500 μm). Results suggest that the lacunar-canalicular intrinsic permeability of mouse bone decreases from 2 to 7 months, with no significant changes from 7 to 12 months. The large indenter tip imposed larger contact sizes and sampled larger ranges of permeabilities, particularly for the old bone. This age-related difference in the distribution was not seen for indents with the smaller radius tip. We conclude that the small tip effectively measured lacunar-canalicular permeability, while larger tip indents were influenced by vascular permeability. Exploring the age-related changes in permeability of bone measured by nanoindentation will lead to a better understanding of the role of fluid flow in mechano-transduction. This understanding may help indicate alterations in bone adaptation and remodeling. Copyright © 2013 Elsevier Ltd. All rights reserved.

Species delimitation in lemurs: multiple genetic loci reveal low levels of species diversity in the genus Cheirogaleus

PubMed Central

Groeneveld, Linn F; Weisrock, David W; Rasoloarison, Rodin M; Yoder, Anne D; Kappeler, Peter M

2009-01-01

Background Species are viewed as the fundamental unit in most subdisciplines of biology. To conservationists this unit represents the currency for global biodiversity assessments. Even though Madagascar belongs to one of the top eight biodiversity hotspots of the world, the taxonomy of its charismatic lemuriform primates is not stable. Within the last 25 years, the number of described lemur species has more than doubled, with many newly described species identified among the nocturnal and small-bodied cheirogaleids. Here, we characterize the diversity of the dwarf lemurs (genus Cheirogaleus) and assess the status of the seven described species, based on phylogenetic and population genetic analysis of mtDNA (cytb + cox2) and three nuclear markers (adora3, fiba and vWF). Results This study identified three distinct evolutionary lineages within the genus Cheirogaleus. Population genetic cluster analyses revealed a further layer of population divergence with six distinct genotypic clusters. Conclusion Based on the general metapopulation lineage concept and multiple concordant data sets, we identify three exclusive groups of dwarf lemur populations that correspond to three of the seven named species: C. major, C. medius and C. crossleyi. These three species were found to be genealogically exclusive in both mtDNA and nDNA loci and are morphologically distinguishable. The molecular and morphometric data indicate that C. adipicaudatus and C. ravus are synonymous with C. medius and C. major, respectively. Cheirogaleus sibreei falls into the C. medius mtDNA clade, but in morphological analyses the membership is not clearly resolved. We do not have sufficient data to assess the status of C. minusculus. Although additional patterns of population differentiation are evident, there are no clear subdivisions that would warrant additional specific status. We propose that ecological and more geographic data should be collected to confirm these results. PMID:19193227

Genomic Imprinting of the M6P/IGF2 Receptor: A Novel Breast Cancer Susceptibility Mechanism

DTIC Science & Technology

2000-07-01

i.e. echidna and platypus ), marsupials (i.e. opossum) and eutherian mammals (i.e. mouse, rat, pig, cow, bat, flying lemur, tree shrew, ringtail lemur...and humans). Our findings demonstrate that M6P/IGF2R is not imprinted in the egg-laying platypus and echidna, whereas it is imprinted in the opossum

The effects of aging on the BTBR mouse model of autism spectrum disorder

PubMed Central

Jasien, Joan M.; Daimon, Caitlin M.; Wang, Rui; Shapiro, Bruce K.; Martin, Bronwen; Maudsley, Stuart

2014-01-01

Autism spectrum disorder (ASD) is a complex heterogeneous neurodevelopmental disorder characterized by alterations in social functioning, communicative abilities, and engagement in repetitive or restrictive behaviors. The process of aging in individuals with autism and related neurodevelopmental disorders is not well understood, despite the fact that the number of individuals with ASD aged 65 and older is projected to increase by over half a million individuals in the next 20 years. To elucidate the effects of aging in the context of a modified central nervous system, we investigated the effects of age on the BTBR T + tf/j mouse, a well characterized and widely used mouse model that displays an ASD-like phenotype. We found that a reduction in social behavior persists into old age in male BTBR T + tf/j mice. We employed quantitative proteomics to discover potential alterations in signaling systems that could regulate aging in the BTBR mice. Unbiased proteomic analysis of hippocampal and cortical tissue of BTBR mice compared to age-matched wild-type controls revealed a significant decrease in brain derived neurotrophic factor and significant increases in multiple synaptic markers (spinophilin, Synapsin I, PSD 95, NeuN), as well as distinct changes in functional pathways related to these proteins, including “Neural synaptic plasticity regulation” and “Neurotransmitter secretion regulation.” Taken together, these results contribute to our understanding of the effects of aging on an ASD-like mouse model in regards to both behavior and protein alterations, though additional studies are needed to fully understand the complex interplay underlying aging in mouse models displaying an ASD-like phenotype. PMID:25225482

Mouse allergen exposure and decreased risk of allergic rhinitis in school-aged children.

PubMed

Jacobs, Tammy S; Forno, Erick; Brehm, John M; Acosta-Pérez, Edna; Han, Yueh-Ying; Blatter, Joshua; Thorne, Peter; Metwali, Nervana; Colón-Semidey, Angel; Alvarez, María; Canino, Glorisa; Celedón, Juan C

2014-12-01

Little is known about exposure to mouse allergen (Mus m 1) and allergic rhinitis (AR). To evaluate the association between mouse allergen exposure and AR in children. We examined the relation between mouse allergen level in house dust and AR in 511 children aged 6 to 14 years in San Juan, Puerto Rico. Study participants were chosen from randomly selected households using a multistage probability sample design. The study protocol included questionnaires, allergy skin testing, and collection of blood and dust samples. AR was defined as current rhinitis symptoms and skin test reactivity to at least one allergen. In the multivariate analyses, mouse allergen level was associated with a 25% decreased odds of AR in participating children (95% confidence interval, 0.62-0.92). Although endotoxin and mouse allergen levels were significantly correlated (r = 0.184, P < .001), the observed inverse association between Mus m 1 and AR was not explained by levels of endotoxin or other markers of microbial or fungal exposure (peptidoglycan and glucan). Mouse allergen exposure is associated with decreased odds of AR in Puerto Rican school-aged children. Copyright © 2014 American College of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.

The mouse as a model organism in aging research: usefulness, pitfalls and possibilities.

PubMed

Vanhooren, Valerie; Libert, Claude

2013-01-01

The mouse has become the favorite mammalian model. Among the many reasons for this privileged position of mice is their genetic proximity to humans, the possibilities of genetically manipulating their genomes and the availability of many tools, mutants and inbred strains. Also in the field of aging, mice have become very robust and reliable research tools. Since laboratory mice have a life expectancy of only a few years, genetic approaches and other strategies for intervening in aging can be tested by examining their effects on life span and aging parameters during the relatively short period of, for example, a PhD project. Moreover, experiments on mice with an extended life span as well as on mice demonstrating signs of (segmental) premature aging, together with genetic mapping strategies, have provided novel insights into the fundamental processes that drive aging. Finally, the results of studies on caloric restriction and pharmacological anti-aging treatments in mice have a high degree of relevance to humans. In this paper, we review a number of recent genetic mapping studies that have yielded novel insights into the aging process. We discuss the value of the mouse as a model for testing interventions in aging, such as caloric restriction, and we critically discuss mouse strains with an extended or a shortened life span as models of aging. Copyright © 2012 Elsevier B.V. All rights reserved.

Profiling caregivers: Hormonal variation underlying allomaternal care in wild red-bellied lemurs, Eulemur rubriventer.

PubMed

Tecot, Stacey R; Baden, Andrea L

2018-05-02

Neuroendocrine evidence suggests that paternal care is mediated by hormonal mechanisms, where hormonal changes in expectant and new fathers facilitate infant care. In species with obligate and extensive paternal care such as humans, androgen levels decline once males are paired and have offspring, and in direct response to offspring care. Facultative infant care is widespread in the Order Primates, but the underlying hormonal mechanisms are largely unknown. We found that wild, red-bellied lemurs living in family groups (two adults and their presumed offspring) varied in the amount of care they provided infants. The more fathers invested in helping infants (measured as a composite of carrying, holding, huddling, grooming, and playing), and specifically the more they huddled and groomed with infants, the higher their fecal androgen (fA) levels, contrary to expectations. Carrying was negatively related to fA levels. Helping by subadults and juveniles was not related to their own fA levels. Elevated fA levels during infant dependence have been observed in other vertebrate species, and are thought to reflect reinvestment in mating rather than investment in dependent offspring. However, red-bellied lemurs do not mate until after infants are weaned, and they have long-term pair-bonds, suggesting that elevated fA levels play a role in offspring care. These results support a growing body of research suggesting that elevated androgen levels do not inhibit protective infant care. Copyright © 2017 Elsevier Inc. All rights reserved.

Mouse models of ageing and their relevance to disease.

PubMed

Kõks, Sulev; Dogan, Soner; Tuna, Bilge Guvenc; González-Navarro, Herminia; Potter, Paul; Vandenbroucke, Roosmarijn E

2016-12-01

Ageing is a process that gradually increases the organism's vulnerability to death. It affects different biological pathways, and the underlying cellular mechanisms are complex. In view of the growing disease burden of ageing populations, increasing efforts are being invested in understanding the pathways and mechanisms of ageing. We review some mouse models commonly used in studies on ageing, highlight the advantages and disadvantages of the different strategies, and discuss their relevance to disease susceptibility. In addition to addressing the genetics and phenotypic analysis of mice, we discuss examples of models of delayed or accelerated ageing and their modulation by caloric restriction. Copyright © 2016 The Authors. Published by Elsevier Ireland Ltd.. All rights reserved.

Caffeine delays oocyte aging and maintains the quality of aged oocytes safely in mouse.

PubMed

Zhang, Xia; Liu, Xiaoyan; Chen, Li; Wu, Dan-Ya; Nie, Zheng-Wen; Gao, Ying-Ying; Miao, Yi-Liang

2017-03-28

Caffeine, as an oocyte aging inhibitor, was used in many different species to control or delay oocyte aging. However, the safety of caffeine and developmental competence of aged oocytes inhibited by caffeine has not been studied systematically. So we detected the spindle morphology, distribution of cortical granules, zona pellucida hardening and pronucleus formation to assess oocyte quality of caffeine treated oocytes. We found that aged oocytes treated by caffeine maintained weak susceptibility to activating stimuli and regained normal competent after aged further 6 hr. Caffeine maintained the spindle morphology, changed cortical granules distribution of aged oocytes and could not prevent zona pellucida hardening. Furthermore, caffeine increased pronucleus formation of aged oocytes and decreased fragmentation after fertilization. These results suggested that caffeine could maintain the quality of aged oocytes safely in mouse.

Treatment of d-galactose induced mouse aging with Lycium barbarum polysaccharides and its mechanism study.

PubMed

Tang, Tao; He, Bixiu

2013-01-01

We evaluated the effects of Lycium barbarum polysaccharides LBP) on D-galactose aging model mouse, and explored its possible mechanism. Kunming mice were randomly divided into the control group, the model group, the high-dose LBP group, and the low-dose LBP group. Except the control group, D-galactose was used for modelling. The drug was administrated when modelling. Mouse behavioural, learning and memory changes were observed, and the contents of lipid peroxidation (LPO), lipofuscin (LF) and monoamine oxidase B (MAO-B) in mouse brain tissue and the weight of immune organs were measured after 6 weeks. Compared with the control group, mouse weight gain in the model group reduced significantly. Compared with model group, after mice drank LBP, the times of electric shock was less than aging mice (in which, the high-dose LBP group, P<0.05), and electric shock incubation period was longer (P<0.01). On Day 45 after modelling and drug administration, the contents of LPO, LF and MAO-B in mouse brain tissue in the model group increased significantly, while those in the drug administration groups decreased significantly. The thymus index in the aging model group decreased significantly; the thymus index and the spleen index in the high-dose LBP group and the low-dose LBP group rebounded significantly (P<0.01). We concluded that LBP has an anti-aging effect on D-galactose induced aging model mouse, and its mechanism may be related with the alleviation of glucose metabolism disorder and the resistance of the generation of lipid peroxide and other substances, which damage cell membrane lipid.

The socio-matrix reloaded: from hierarchy to dominance profile in wild lemurs.

PubMed

Norscia, Ivan; Palagi, Elisabetta

2015-01-01

Dominance hierarchy influences the life quality of social animals, and its definition should in principle be based on the outcome of agonistic interactions. However, defining and comparing the dominance profile of social groups is difficult due to the different dominance measures used and because no one measure explains it all. We applied different analytical methods to winner-loser sociomatrices to determine the dominance profile of five groups of wild lemurs (species: Lemur catta, Propithecus verreauxi, and Eulemur rufus x collaris) from the Berenty forest (Madagascar). They are an excellent study model because they share the same habitat and an apparently similar dominance profile: linear hierarchy and female dominance. Data were collected over more than 1200 h of observation. Our approach included four steps: (1) by applying the binary dyadic dominance relationship method (I&SI) on either aggressions or supplant sociomatrices we verified whether hierarchy was aggression or submission based; (2) by calculating normalized David's scores and measuring steepness from aggression sociomatrices we evaluated whether hierarchy was shallow or steep; (3) by comparing the ranking orders obtained with methods 1 and 2 we assessed whether hierarchy was consistent or not; and (4) by assessing triangle transitivity and comparing it with the linearity index and the level of group cohesion we determined if hierarchy was more or less cohesive. Our results show that L. catta groups have got a steep, consistent, highly transitive and cohesive hierarchy. P. verreauxi groups are characterized by a moderately steep and consistent hierarchy, with variable levels of triangle transitivity and cohesion. E. rufus x collaris group possesses a shallow and inconsistent hierarchy, with lower (but not lowest) levels of transitivity and cohesion. A multiple analytical approach on winner-loser sociomatrices other than leading to an in-depth description of the dominance profile, allows intergroup

The socio-matrix reloaded: from hierarchy to dominance profile in wild lemurs

PubMed Central

Norscia, Ivan

2015-01-01

Dominance hierarchy influences the life quality of social animals, and its definition should in principle be based on the outcome of agonistic interactions. However, defining and comparing the dominance profile of social groups is difficult due to the different dominance measures used and because no one measure explains it all. We applied different analytical methods to winner-loser sociomatrices to determine the dominance profile of five groups of wild lemurs (species: Lemur catta, Propithecus verreauxi, and Eulemur rufus x collaris) from the Berenty forest (Madagascar). They are an excellent study model because they share the same habitat and an apparently similar dominance profile: linear hierarchy and female dominance. Data were collected over more than 1200 h of observation. Our approach included four steps: (1) by applying the binary dyadic dominance relationship method (I&SI) on either aggressions or supplant sociomatrices we verified whether hierarchy was aggression or submission based; (2) by calculating normalized David’s scores and measuring steepness from aggression sociomatrices we evaluated whether hierarchy was shallow or steep; (3) by comparing the ranking orders obtained with methods 1 and 2 we assessed whether hierarchy was consistent or not; and (4) by assessing triangle transitivity and comparing it with the linearity index and the level of group cohesion we determined if hierarchy was more or less cohesive. Our results show that L. catta groups have got a steep, consistent, highly transitive and cohesive hierarchy. P. verreauxi groups are characterized by a moderately steep and consistent hierarchy, with variable levels of triangle transitivity and cohesion. E. rufus x collaris group possesses a shallow and inconsistent hierarchy, with lower (but not lowest) levels of transitivity and cohesion. A multiple analytical approach on winner-loser sociomatrices other than leading to an in-depth description of the dominance profile, allows intergroup

Age-dependent phenotypic characteristics of a triple transgenic mouse model of Alzheimer disease.

PubMed

Pietropaolo, Susanna; Feldon, Joram; Yee, Benjamin K

2008-08-01

The triple-transgenic mouse line (3 x Tg-AD) harboring PS1M146V, APPSwe, and taup301L transgenes represents the only transgenic model for Alzheimer's disease (AD) to date capturing both beta-amyloid and tau neuropathology. The present study provides an extensive behavioral characterization of the 3 x Tg-AD mouse line, evaluating the emergence of noncognitive and cognitive AD-like symptoms at two ages corresponding to the early (6-7 months) and advanced (12-13 months) stages of AD-pathology. Enhanced responsiveness to aversive stimulation was detected in mutant mice at both ages: the 3 x Tg-AD genotype enhanced acoustic startle response and facilitated performance in the cued-version of the water maze. These noncognitive phenotypes were accompanied by hyperactivity and reduced locomotor habituation in the open field at the older age. Signs of cognitive aberrations were also detected at both ages, but they were limited to associative learning. The present study suggests that this popular transgenic mouse model of AD has clear phenotypes beyond the cognitive domain, and their potential relationship to the cognitive phenotypes should be further explored.

Brain perfusion SPECT in the mouse: normal pattern according to gender and age.

PubMed

Apostolova, Ivayla; Wunder, Andreas; Dirnagl, Ulrich; Michel, Roger; Stemmer, Nina; Lukas, Mathias; Derlin, Thorsten; Gregor-Mamoudou, Betina; Goldschmidt, Jürgen; Brenner, Winfried; Buchert, Ralph

2012-12-01

Regional cerebral blood flow (rCBF) is a useful surrogate marker of neuronal activity and a parameter of primary interest in the diagnosis of many diseases. The increasing use of mouse models spawns the demand for in vivo measurement of rCBF in the mouse. Small animal SPECT provides excellent spatial resolution at adequate sensitivity and is therefore a promising tool for imaging the mouse brain. This study evaluates the feasibility of mouse brain perfusion SPECT and assesses the regional pattern of normal Tc-99m-HMPAO uptake and the impact of age and gender. Whole-brain kinetics was compared between Tc-99m-HMPAO and Tc-99m-ECD using rapid dynamic planar scans in 10 mice. Assessment of the regional uptake pattern was restricted to the more suitable tracer, HMPAO. Two HMPAO SPECTs were performed in 18 juvenile mice aged 7.5 ± 1.5weeks, and in the same animals at young adulthood, 19.1 ± 4.0 weeks (nanoSPECT/CTplus, general purpose mouse apertures: 1.2kcps/MBq, 0.7mm FWHM). The 3-D MRI Digital Atlas Database of an adult C57BL/6J mouse brain was used for region-of-interest (ROI) analysis. SPECT images were stereotactically normalized using SPM8 and a custom made, left-right symmetric HMPAO template in atlas space. For testing lateral asymmetry, each SPECT was left-right flipped prior to stereotactical normalization. Flipped and unflipped SPECTs were compared by paired testing. Peak brain uptake was similar for ECD and HMPAO: 1.8 ± 0.2 and 2.1 ± 0.6 %ID (p=0.357). Washout after the peak was much faster for ECD than for HMPAO: 24 ± 7min vs. 4.6 ± 1.7h (p=0.001). The general linear model for repeated measures with gender as an intersubject factor revealed an increase in relative HMPAO uptake with age in the neocortex (p=0.018) and the hippocampus (p=0.012). A decrease was detected in the midbrain (p=0.025). Lateral asymmetry, with HMPAO uptake larger in the left hemisphere, was detected primarily in the neocortex, both at juvenile age (asymmetry index AI=2.7 ± 1

Are personality differences in a small iteroparous mammal maintained by a life-history trade-off?

PubMed Central

Dammhahn, Melanie

2012-01-01

Despite increasing interest, animal personality is still a puzzling phenomenon. Several theoretical models have been proposed to explain intraindividual consistency and interindividual variation in behaviour, which have been primarily supported by qualitative data and simulations. Using an empirical approach, I tested predictions of one main life-history hypothesis, which posits that consistent individual differences in behaviour are favoured by a trade-off between current and future reproduction. Data on life-history were collected for individuals of a natural population of grey mouse lemurs (Microcebus murinus). Using open-field and novel-object tests, I quantified variation in activity, exploration and boldness for 117 individuals over 3 years. I found systematic variation in boldness between individuals of different residual reproductive value. Young males with low current but high expected future fitness were less bold than older males with high current fecundity, and males might increase in boldness with age. Females have low variation in assets and in boldness with age. Body condition was not related to boldness and only explained marginal variation in exploration. Overall, these data indicate that a trade-off between current and future reproduction might maintain personality variation in mouse lemurs, and thus provide empirical support of this life-history trade-off hypothesis. PMID:22398164

Quantitative Aging Pattern in Mouse Urine Vapor as Measured by Gas-Liquid Chromatography

NASA Technical Reports Server (NTRS)

Robinson, Arthur B.; Dirren, Henri; Sheets, Alan; Miquel, Jaime; Lundgren, Paul R.

1975-01-01

We have discovered a quantitative aging pattern in mouse urine vapor. The diagnostic power of the pattern has been found to be high. We hope that this pattern will eventually allow quantitative estimates of physiological age and some insight into the biochemistry of aging.

Meta-Profiles of Gene Expression during Aging: Limited Similarities between Mouse and Human and an Unexpectedly Decreased Inflammatory Signature

PubMed Central

Swindell, William R.; Johnston, Andrew; Sun, Liou; Xing, Xianying; Fisher, Gary J.; Bulyk, Martha L.; Elder, James T.; Gudjonsson, Johann E.

2012-01-01

Background Skin aging is associated with intrinsic processes that compromise the structure of the extracellular matrix while promoting loss of functional and regenerative capacity. These processes are accompanied by a large-scale shift in gene expression, but underlying mechanisms are not understood and conservation of these mechanisms between humans and mice is uncertain. Results We used genome-wide expression profiling to investigate the aging skin transcriptome. In humans, age-related shifts in gene expression were sex-specific. In females, aging increased expression of transcripts associated with T-cells, B-cells and dendritic cells, and decreased expression of genes in regions with elevated Zeb1, AP-2 and YY1 motif density. In males, however, these effects were contrasting or absent. When age-associated gene expression patterns in human skin were compared to those in tail skin from CB6F1 mice, overall human-mouse correspondence was weak. Moreover, inflammatory gene expression patterns were not induced with aging of mouse tail skin, and well-known aging biomarkers were in fact decreased (e.g., Clec7a, Lyz1 and Lyz2). These unexpected patterns and weak human-mouse correspondence may be due to decreased abundance of antigen presenting cells in mouse tail skin with age. Conclusions Aging is generally associated with a pro-inflammatory state, but we have identified an exception to this pattern with aging of CB6F1 mouse tail skin. Aging therefore does not uniformly heighten inflammatory status across all mouse tissues. Furthermore, we identified both intercellular and intracellular mechanisms of transcriptome aging, including those that are sex- and species-specific. PMID:22413003

The use of urinary proteomics in the assessment of suitability of mouse models for ageing.

PubMed

Nkuipou-Kenfack, Esther; Schanstra, Joost P; Bajwa, Seerat; Pejchinovski, Martin; Vinel, Claire; Dray, Cédric; Valet, Philippe; Bascands, Jean-Loup; Vlahou, Antonia; Koeck, Thomas; Borries, Melanie; Busch, Hauke; Bechtel-Walz, Wibke; Huber, Tobias B; Rudolph, Karl L; Pich, Andreas; Mischak, Harald; Zürbig, Petra

2017-01-01

Ageing is a complex process characterised by a systemic and progressive deterioration of biological functions. As ageing is associated with an increased prevalence of age-related chronic disorders, understanding its underlying molecular mechanisms can pave the way for therapeutic interventions and managing complications. Animal models such as mice are commonly used in ageing research as they have a shorter lifespan in comparison to humans and are also genetically close to humans. To assess the translatability of mouse ageing to human ageing, the urinary proteome in 89 wild-type (C57BL/6) mice aged between 8-96 weeks was investigated using capillary electrophoresis coupled to mass spectrometry (CE-MS). Using age as a continuous variable, 295 peptides significantly correlated with age in mice were identified. To investigate the relevance of using mouse models in human ageing studies, a comparison was performed with a previous correlation analysis using 1227 healthy subjects. In mice and humans, a decrease in urinary excretion of fibrillar collagens and an increase of uromodulin fragments was observed with advanced age. Of the 295 peptides correlating with age, 49 had a strong homology to the respective human age-related peptides. These ortholog peptides including several collagen (N = 44) and uromodulin (N = 5) fragments were used to generate an ageing classifier that was able to discriminate the age among both wild-type mice and healthy subjects. Additionally, the ageing classifier depicted that telomerase knock-out mice were older than their chronological age. Hence, with a focus on ortholog urinary peptides mouse ageing can be translated to human ageing.

Personality and performance are affected by age and early life parameters in a small primate.

PubMed

Zablocki-Thomas, Pauline B; Herrel, Anthony; Hardy, Isabelle; Rabardel, Lucile; Perret, Martine; Aujard, Fabienne; Pouydebat, Emmanuelle

2018-05-01

A whole suite of parameters is likely to influence the behavior and performance of individuals as adults, including correlations between phenotypic traits or an individual's developmental context. Here, we ask the question whether behavior and physical performance traits are correlated and how early life parameters such as birth weight, litter size, and growth can influence these traits as measured during adulthood. We studied 486 captive gray mouse lemurs ( Microcebus murinus ) and measured two behavioral traits and two performance traits potentially involved in two functions: exploration behavior with pull strength and agitation score with bite force. We checked for the existence of behavioral consistency in behaviors and explored correlations between behavior, performance, morphology. We analyzed the effect of birth weight, growth, and litter size, while controlling for age, sex, and body weight. Behavior and performance were not correlated with one another, but were both influenced by age. Growth rate had a positive effect on adult morphology, and birth weight significantly affected emergence latency and bite force. Grip strength was not directly affected by early life traits, but bite performance and exploration behavior were impacted by birth weight. This study shows how early life parameters impact personality and performance.

The senescence accelerated mouse prone 8 (SAMP8): A novel murine model for cardiac aging.

PubMed

Karuppagounder, Vengadeshprabhu; Arumugam, Somasundaram; Babu, Sahana Suresh; Palaniyandi, Suresh S; Watanabe, Kenichi; Cooke, John P; Thandavarayan, Rajarajan A

2017-05-01

Because cardiovascular disease remains the major cause of mortality and morbidity world-wide, there remains a compelling need for new insights and novel therapeutic avenues. In this regard, the senescence-accelerated mouse prone 8 (SAMP8) line is a particularly good model for studying the effects of aging on cardiovascular health. Accumulating evidence suggests that this model may shed light on age-associated cardiac and vascular dysfunction and disease. These animals manifest evidence of inflammation, oxidative stress and adverse cardiac remodeling that may recapitulate processes involved in human disease. Early alterations in oxidative damage promote endoplasmic reticulum stress to trigger apoptosis and cytokine production in this genetically susceptible mouse strain. Conversely, pharmacological treatments that reduce inflammation and oxidative stress improve cardiac function in these animals. Therefore, the SAMP8 mouse model provides an exciting opportunity to expand our knowledge of aging in cardiovascular disease and the potential identification of novel targets of treatment. Herein, we review the previous studies performed in SAMP8 mice that provide insight into age-related cardiovascular alterations. Copyright © 2016 Elsevier B.V. All rights reserved.

Isolation Efficiency of Mouse Pancreatic Stem Cells Is Age Dependent.

PubMed

Kuise, Takashi; Noguchi, Hirofumi; Saitoh, Issei; Kataoka, Hitomi Usui; Watanabe, Masami; Noguchi, Yasufumi; Fujiwara, Toshiyoshi

2013-11-10

Mouse pancreatic stem cells have been isolated from mouse pancreata. This study evaluated the efficacy of isolating mouse pancreatic stem cells using mice of different ages. The pancreata of newborn mice, 8-week-old mice, and 24-week-old mice were harvested and digested by using collagenase. The "duct-like" cells in the digested pancreatic tissue were then inoculated into 96-well plates, cloned by limiting dilution, and cultured in DMEM with 20% FBS. Pancreatic stem cells were isolated from the pancreata of all newborn mice, while cells could only be isolated from 10% of the pancreata of 8-week-old mice and could not be isolated from the pancreata of any 24-week-old mice. These data suggest that young mice may have some pancreatic stem cells and that older mice may only have a few pancreatic stem cells. These data also indicate that it is extremely difficult to isolate pancreatic stem cells from older mice, suggesting that future research focus its efforts on finding methods of isolating pancreatic stem cells from adult mice.

Senescence or selective disappearance? Age trajectories of body mass in wild and captive populations of a small-bodied primate.

PubMed

Hämäläinen, Anni; Dammhahn, Melanie; Aujard, Fabienne; Eberle, Manfred; Hardy, Isabelle; Kappeler, Peter M; Perret, Martine; Schliehe-Diecks, Susanne; Kraus, Cornelia

2014-09-22

Classic theories of ageing consider extrinsic mortality (EM) a major factor in shaping longevity and ageing, yet most studies of functional ageing focus on species with low EM. This bias may cause overestimation of the influence of senescent declines in performance over condition-dependent mortality on demographic processes across taxa. To simultaneously investigate the roles of functional senescence (FS) and intrinsic, extrinsic and condition-dependent mortality in a species with a high predation risk in nature, we compared age trajectories of body mass (BM) in wild and captive grey mouse lemurs (Microcebus murinus) using longitudinal data (853 individuals followed through adulthood). We found evidence of non-random mortality in both settings. In captivity, the oldest animals showed senescence in their ability to regain lost BM, whereas no evidence of FS was found in the wild. Overall, captive animals lived longer, but a reversed sex bias in lifespan was observed between wild and captive populations. We suggest that even moderately condition-dependent EM may lead to negligible FS in the wild. While high EM may act to reduce the average lifespan, this evolutionary process may be counteracted by the increased fitness of the long-lived, high-quality individuals. © 2014 The Author(s) Published by the Royal Society. All rights reserved.

Dental development in Megaladapis edwardsi (Primates, Lemuriformes): implications for understanding life history variation in subfossil lemurs.

PubMed

Schwartz, Gary T; Mahoney, Patrick; Godfrey, Laurie R; Cuozzo, Frank P; Jungers, William L; Randria, Gisèle F N

2005-12-01

Teeth grow incrementally and preserve within them a record of that incremental growth in the form of microscopic growth lines. Studying dental development in extinct and extant primates, and its relationship to adult brain and body size as well as other life history and ecological parameters (e.g., diet, somatic growth rates, gestation length, age at weaning), holds the potential to yield unparalleled insights into the life history profiles of fossil primates. Here, we address the absolute pace of dental development in Megaladapis edwardsi, a giant extinct lemur of Madagascar. By examining the microstructure of the first and developing second molars in a juvenile individual, we establish a chronology of molar crown development for this specimen (M1 CFT = 1.04 years; M2 CFT = 1.42 years) and determine its age at death (1.39 years). Microstructural data on prenatal M1 crown formation time allow us to calculate a minimum gestation length of 0.54 years for this species. Postnatal crown and root formation data allow us to estimate its age at M1 emergence (approximately 0.9 years) and to establish a minimum age for M2 emergence (>1.39 years). Finally, using reconstructions or estimates (drawn elsewhere) of adult body mass, brain size, and diet in Megaladapis, as well as the eruption sequence of its permanent teeth, we explore the efficacy of these variables in predicting the absolute pace of dental development in this fossil species. We test competing explanations of variation in crown formation timing across the order Primates. Brain size is the best single predictor of crown formation time in primates, but other variables help to explain the variation.

SIRT1, 2, 3 protect mouse oocytes from postovulatory aging.

PubMed

Zhang, Teng; Zhou, Yang; Li, Li; Wang, Hong-Hui; Ma, Xue-Shan; Qian, Wei-Ping; Shen, Wei; Schatten, Heide; Sun, Qing-Yuan

2016-04-01

The quality of metaphase II oocytes will undergo a time-dependent deterioration following ovulation as the result of the oocyte aging process. In this study, we determined that the expression of sirtuin family members (SIRT1, 2, 3) was dramatically reduced in mouse oocytes aged in vivo or in vitro. Increased intracellular ROS was observed when SIRT1, 2, 3 activity was inhibited. Increased frequency of spindle defects and disturbed distribution of mitochondria were also observed in MII oocytes aged in vitro after treatment with Nicotinamide (NAM), indicating that inhibition of SIRT1, 2, 3 may accelerate postovulatory oocyte aging. Interestingly, when MII oocytes were exposed to caffeine, the decline of SIRT1, 2, 3 mRNA levels was delayed and the aging-associated defective phenotypes could be improved. The results suggest that the SIRT1, 2, 3 pathway may play a potential protective role against postovulatory oocyte aging by controlling ROS generation.

Root sepsis associated with insect-dwelling Sebaldella termitidis in a lesser dwarf lemur (Cheirogaleus medius).

PubMed

Eisenberg, Tobias; Glaeser, Stefanie P; Kämpfer, Peter; Schauerte, Nicole; Geiger, Christina

2015-12-01

Sebaldella termitidis is a rare fastidious microorganism of the Leptotrichiaceae family. A variety of closely related species are associated with severe and even life-threatening disease in humans and animals, such as Streptobacillus moniliformis, the etiological organism of rat-bite fever as well as members of Leptotrichia spp. and Sneathia sanguinegens, which have been reported from cases of septicaemia. In contrast, since its description some 50 years ago, S. ermitidis has so far never been reported as a vertebrate pathogen, nor has it been found aside from its natural termite host. A lesser dwarf lemur was presented with unilateral facial inflammation originating from rotten maxillary teeth and septic root abscess. Surgical intervention and root extraction significantly improved the clinical cause in that a pus-filled cavity underneath the right eye could be drained, sampled and flushed. Bacteria displaying substantial characteristics of S. termitidis were cultured from the sampled pus. Morphological features observed included strictly anaerobic regular Gram-negative rods. Significant shared biochemical properties included negative reactions for cytochrome oxidase, catalase, urease, nitrate reduction and indole production. Furthermore, 16S rRNA gene sequencing revealed 99.9 % sequence homology to the S. termitidis type strain NCTC 11300(T), from which it, nevertheless, differed with respect to rep and rep- and RAPD-PCR profiles. An affiliation of the lemur isolate described in this study with the type strain of S. termitidis as well as a clear discrimination from other members of the Leptotrichiaceae could also be confirmed by matrix-assisted laser desorption/ionization time-of flight mass spectrometry and Fourier transform-infrared spectroscopy. This is the first evidence for clinical disease caused by S. termitidis in a vertebrate species indicating a broader host spectrum of this rarely encountered microorganism.

Structural characterization of neutral and acidic oligosaccharides in the milks of strepsirrhine primates: greater galago, aye-aye, Coquerel's sifaka and mongoose lemur.

PubMed

Taufik, Epi; Fukuda, Kenji; Senda, Akitsugu; Saito, Tadao; Williams, Cathy; Tilden, Chris; Eisert, Regina; Oftedal, Olav; Urashima, Tadasu

2012-04-01

The structures of milk oligosaccharides were characterized for four strepsirrhine primates to examine the extent to which they resemble milk oligosaccharides in other primates. Neutral and acidic oligosaccharides were isolated from milk of the greater galago (Galagidae: Otolemur crassicaudatus), aye-aye (Daubentoniidae: Daubentonia madagascariensis), Coquerel's sifaka (Indriidae: Propithecus coquereli) and mongoose lemur (Lemuridae: Eulemur mongoz), and their chemical structures were characterized by (1)H-NMR spectroscopy. The oligosaccharide patterns observed among strepsirrhines did not appear to correlate to phylogeny, sociality or pattern of infant care. Both type I and type II neutral oligosaccharides were found in the milk of the aye-aye, but type II predominate over type I. Only type II oligosaccharides were identified in other strepsirrhine milks. α3'-GL (isoglobotriose, Gal(α1-3)Gal(β1-4)Glc) was found in the milks of Coquerel's sifaka and mongoose lemur, which is the first report of this oligosaccharide in the milk of any primate species. 2'-FL (Fuc(α1-2)Gal(β1-4)Glc) was found in the milk of an aye-aye with an ill infant. Oligosaccharides containing the Lewis x epitope were found in aye-aye and mongoose lemur milk. Among acidic oligosaccharides, 3'-N-acetylneuraminyllactose (3'-SL-NAc, Neu5Ac(α2-3)Gal(β1-4)Glc) was found in all studied species, whereas 6'-N-acetylneuraminyllactose (6'-SL-NAc, Neu5Ac(α2-6)Gal(β1-4)Glc) was found in all species except greater galago. Greater galago milk also contained 3'-N-glycolylneuraminyllactose (3'-SL-NGc, Neu5Gc(α2-3)Gal(β1-4)Glc). The finding of a variety of neutral and acidic oligosaccharides in the milks of strepsirrhines, as previously reported for haplorhines, suggests that such constituents are ancient rather than derived features, and are as characteristic of primate lactation is the classic disaccharide, lactose.

Assessment of Polycyclic Aromatic Hydrocarbon Contamination of Breeding Pools Utilized by the Puerto Rican Crested Toad, Peltophryne lemur

PubMed Central

Gjeltema, Jenessa; Stoskopf, Michael; Shea, Damian; De Voe, Ryan

2012-01-01

Habitat preservation and management may play an important role in the conservation of the Puerto Rican crested toad, Peltophryne lemur, due to this species' small geographic range and declining native wild population. Bioavailable water concentrations of Polycyclic Aromatic Hydrocarbon (PAH) contaminants within breeding pools at 3 sites were established using Passive Sampling Devices (PSDs) and gas chromatography-mass spectrometry (GC/MS). A more diverse population of PAH analytes were found in higher concentrations at the breeding site that allowed direct vehicular access, but calculated risk quotients indicated low risk to toad reproduction associated with the current PAH analyte levels. PMID:23762634

The Relevance of Mouse Models for Investigating Age-Related Bone Loss in Humans

PubMed Central

2013-01-01

Mice are increasingly used for investigation of the pathophysiology of osteoporosis because their genome is easily manipulated, and their skeleton is similar to that of humans. Unlike the human skeleton, however, the murine skeleton continues to grow slowly after puberty and lacks osteonal remodeling of cortical bone. Yet, like humans, mice exhibit loss of cancellous bone, thinning of cortical bone, and increased cortical porosity with advancing age. Histologic evidence in mice and humans alike indicates that inadequate osteoblast-mediated refilling of resorption cavities created during bone remodeling is responsible. Mouse models of progeria also show bone loss and skeletal defects associated with senescence of early osteoblast progenitors. Additionally, mouse models of atherosclerosis, which often occurs in osteoporotic participants, also suffer bone loss, suggesting that common diseases of aging share pathophysiological pathways. Knowledge of the causes of skeletal fragility in mice should therefore be applicable to humans if inherent limitations are recognized. PMID:23689830

Ageing and gastrointestinal sensory function: altered colonic mechanosensory and chemosensory function in the aged mouse

PubMed Central

Keating, Christopher; Nocchi, Linda; Yu, Yang; Donovan, Jemma; Grundy, David

2016-01-01

Key points Remarkably little is known about how age affects the sensory signalling pathways in the gastrointestinal tract despite age‐related gastrointestinal dysfunction being a prime cause of morbidity amongst the elderly populationHigh‐threshold gastrointestinal sensory nerves play a key role in signalling distressing information from the gut to the brain.We found that ageing is associated with attenuated high‐threshold afferent mechanosensitivity in the murine colon, and associated loss of TRPV1 channel function.These units have the capacity to sensitise in response to injurious events, and their loss in ageing may predispose the elderly to lower awareness of GI injury or disease. Abstract Ageing has a profound effect upon gastrointestinal function through mechanisms that are poorly understood. Here we investigated the effect of age upon gastrointestinal sensory signalling pathways in order to address the mechanisms underlying these changes. In vitro mouse colonic and jejunal preparations with attached splanchnic and mesenteric nerves were used to study mechanosensory and chemosensory afferent function in 3‐, 12‐ and 24‐month‐old C57BL/6 animals. Quantitative RT‐PCR was used to investigate mRNA expression in colonic tissue and dorsal root ganglion (DRG) cells isolated from 3‐ and 24‐month animals, and immunohistochemistry was used to quantify the number of 5‐HT‐expressing enterochromaffin (EC) cells. Colonic and jejunal afferent mechanosensory function was attenuated with age and these effects appeared earlier in the colon compared to the jejunum. Colonic age‐related loss of mechanosensory function was more pronounced in high‐threshold afferents compared to low‐threshold afferents. Chemosensory function was attenuated in the 24‐month colon, affecting TRPV1 and serotonergic signalling pathways. High‐threshold mechanosensory afferent fibres and small‐diameter DRG neurons possessed lower functional TRPV1 receptor responses

Metabolic changes over the course of aging in a mouse model of tau deposition

PubMed Central

Joly-Amado, Aurélie; Serraneau, Karisa S.; Brownlow, Milene; Marín de Evsikova, Caralina; Speakman, John R.; Gordon, Marcia N.; Morgan, Dave

2016-01-01

Weight loss and food intake disturbances that often precede cognitive decline and diagnosis have been extensively reported in Alzheimer’s disease patients. Previously, we observed that transgenic mice overexpressing tau seemed to eat more food, yet weigh less than non-transgenic littermates. Thus the present longitudinal study measured the time course of changes in metabolic state over the lifespan of the tau depositing Tg4510 mouse model of tau deposition. Although body weight was comparable to non-transgenic littermates at 2 months of age, Tg4510 mice weighed less at older ages. This was accompanied by the accumulation of tau pathology and by dramatically increased activity in all phases of the 24-hour cycle. Resting metabolic rate was also increased at 7 months of age. At 12 months near the end of the Tg4510 lifespan, there was a wasting phase, with a considerable decrease of resting metabolic rate, although hyperactivity was maintained. These diverse changes in metabolism in a mouse model of tau deposition are discussed in the context of known changes in energy metabolism in Alzheimer’s disease. PMID:27318134

Brown skin disease: A syndrome of dysecdysis in Puerto Rican crested toads (Peltophryne lemur).

PubMed

Crawshaw, Graham; Pienkowski, Maria; Lentini, Andrew; Dutton, Christopher; Delnatte, Pauline; Russell, Deanna; Berkvens, Charlene; Barker, Ian; Smith, Dale

2014-01-01

The endangered Puerto Rican crested toad (Peltophryne [Bufo] lemur) has been held and bred in zoos for release into protected areas in Puerto Rico since 1982. In 2004, several cases of a novel syndrome of skin changes in toads were noticed at the Toronto Zoo. A total of 21 toads were found to have similar lesions and the condition has been seen in several other groups of toads in subsequent years. Affected toads show an uncharacteristic sheen of dark-brown leathery skin, followed by recurring dysecdysis, reduced appetite, weight loss, and death from secondary causes. Histologically the condition is characterized by epithelial hyperplasia and hyperkeratosis, ulceration, and the presence of superficial mats of bacterial and fungal agents. No etiology has been identified and to date toads have not permanently responded to treatment with various pharmaceutical and nutritional therapies. © 2014 Wiley Periodicals, Inc.

Social behaviour and gut microbiota in red-bellied lemurs (Eulemur rubriventer): In search of the role of immunity in the evolution of sociality.

PubMed

Raulo, Aura; Ruokolainen, Lasse; Lane, Avery; Amato, Katherine; Knight, Rob; Leigh, Steven; Stumpf, Rebecca; White, Bryan; Nelson, Karen E; Baden, Andrea L; Tecot, Stacey R

2018-03-01

Vertebrate gut microbiota form a key component of immunity and a dynamic link between an individual and the ecosystem. Microbiota might play a role in social systems as well, because microbes are transmitted during social contact and can affect host behaviour. Combining methods from behavioural and molecular research, we describe the relationship between social dynamics and gut microbiota of a group-living cooperative species of primate, the red-bellied lemur (Eulemur rubriventer). Specifically, we ask whether patterns of social contact (group membership, group size, position in social network, individual sociality) are associated with patterns of gut microbial composition (diversity and similarity) between individuals and across time. Red-bellied lemurs were found to have gut microbiota with slight temporal fluctuations and strong social group-specific composition. Contrary to expectations, individual sociality was negatively associated with gut microbial diversity. However, position within the social network predicted gut microbial composition. These results emphasize the role of the social environment in determining the microbiota of adult animals. Since social transmission of gut microbiota has the potential to enhance immunity, microbiota might have played an escalating role in the evolution of sociality. © 2017 The Authors. Journal of Animal Ecology © 2017 British Ecological Society.

Phylogeographic analysis of the true lemurs (genus Eulemur) underlines the role of river catchments for the evolution of micro-endemism in Madagascar.

PubMed

Markolf, Matthias; Kappeler, Peter M

2013-11-14

Due to its remarkable species diversity and micro-endemism, Madagascar has recently been suggested to serve as a biogeographic model region. However, hypothesis-based tests of various diversification mechanisms that have been proposed for the evolution of the island's micro-endemic lineages are still limited. Here, we test the fit of several diversification hypotheses with new data on the broadly distributed genus Eulemur using coalescent-based phylogeographic analyses. Time-calibrated species tree analyses and population genetic clustering resolved the previously polytomic species relationships among eulemurs. The most recent common ancestor of eulemurs was estimated to have lived about 4.45 million years ago (mya). Divergence date estimates furthermore suggested a very recent diversification among the members of the "brown lemur complex", i.e. former subspecies of E. fulvus, during the Pleistocene (0.33-1.43 mya). Phylogeographic model comparisons of past migration rates showed significant levels of gene flow between lineages of neighboring river catchments as well as between eastern and western populations of the redfronted lemur (E. rufifrons). Together, our results are concordant with the centers of endemism hypothesis (Wilmé et al. 2006, Science 312:1063-1065), highlight the importance of river catchments for the evolution of Madagascar's micro-endemic biota, and they underline the usefulness of testing diversification mechanisms using coalescent-based phylogeographic methods.

Thermal Stimulation of the Retina Reduces Bruch's Membrane Thickness in Age Related Macular Degeneration Mouse Models.

PubMed

Tode, Jan; Richert, Elisabeth; Koinzer, Stefan; Klettner, Alexa; von der Burchard, Claus; Brinkmann, Ralf; Lucius, Ralph; Roider, Johann

2018-05-01

To investigate the effect of thermal stimulation of the retina (TS-R) on Bruch's membrane (BrM) thickness in age-related macular degeneration (AMD) mouse models as a novel concept for the prophylaxis and treatment of dry AMD. Two knockout AMD mouse models, B6.129P2-Apoe tm1Unc /J (ApoE-/-) and B6.129X1-Nfe2I2 tm1Ywk /J (NRF2-/-), were chosen. One randomized eye of each mouse in four different groups (two of different age, two of different genotype) of five mice was treated by TS-R (532 nm, 10-ms duration, 50-μm spot size), the fellow eye served as control. Laser power was titrated to barely visible laser burns, then reduced by 70% to guarantee for thermal elevation without damage to the neuroretina, then applied uniformly to the murine retina. Fundus, optical coherence tomography (OCT), and fluorescein angiography (FLA) images were obtained at the day of treatment and 1 month after treatment. Eyes were enucleated thereafter to analyze BrM thickness by transmission electron microscopy (TEM) in a standardized blinded manner. Fundus images revealed that all ApoE-/- and NRF2-/- mice had AMD associated retinal alterations. BrM thickness was increased in untreated controls of both mouse models. Subvisible TS-R laser spots were not detectable by fundus imaging, OCT, or FLA 2 hours or 1 month after laser treatment. TEM revealed a significant reduction of BrM thickness in laser-treated eyes of all four groups compared to their fellow control eyes. TS-R reduces BrM thickness in AMD mouse models ApoE-/- and NRF2-/- without damage to the neuroretina. It may become a prophylactic or even therapeutic treatment option for dry AMD. TS-R may become a prophylactic or even therapeutic treatment option for dry AMD.

New distributional records and conservation implications for the critically endangered greater bamboo lemur Prolemur simus.

PubMed

Rakotonirina, Laingoniaina; Rajaonson, Andry; Ratolojanahary, Tianasoa; Rafalimandimby, Jean; Fanomezantsoa, Prosper; Ramahefasoa, Bellarmin; Rasolofoharivelo, Tovonanahary; Ravaloharimanitra, Maholy; Ratsimbazafy, Jonah; Dolch, Rainer; King, Tony

2011-01-01

To improve our knowledge of the distribution of the critically endangered greater bamboo lemur Prolemur simus, we surveyed 6 sites in eastern Madagascar. We found its characteristic feeding signs at 5 sites and made a direct sighting at one of these. One site represents a northern extension of 45 km of the known extant range of the species. Two sites are located in a forest corridor approximately halfway between the previously known southern and northern populations, therefore suggesting a broadly continuous distribution of the species within its range rather than the previously suspected distribution of two distinct populations separated by a distance of over 200 km. Our results illustrate the benefit of species-focussed surveys in determining the true distribution of endangered species, a realistic measure which is necessary in order to assess their current status and to prioritise long-term conservation interventions. Copyright © 2011 S. Karger AG, Basel.

Vitamin C mediates chemical aging of lens crystallins by the Maillard reaction in a humanized mouse model

PubMed Central

Fan, Xingjun; Reneker, Lixing W.; Obrenovich, Mark E.; Strauch, Christopher; Cheng, Rongzhu; Jarvis, Simon M.; Ortwerth, Beryl J.; Monnier, Vincent M.

2006-01-01

Senile cataracts are associated with progressive oxidation, fragmentation, cross-linking, insolubilization, and yellow pigmentation of lens crystallins. We hypothesized that the Maillard reaction, which leads browning and aroma development during the baking of foods, would occur between the lens proteins and the highly reactive oxidation products of vitamin C. To test this hypothesis, we engineered a mouse that selectively overexpresses the human vitamin C transporter SVCT2 in the lens. Consequently, lenticular levels of vitamin C and its oxidation products were 5- to 15-fold elevated, resulting in a highly compressed aging process and accelerated formation of several protein-bound advanced Maillard reaction products identical with those of aging human lens proteins. These data strongly implicate vitamin C in lens crystallin aging and may serve as a model for protein aging in other tissues particularly rich in vitamin C, such as the hippocampal neurons and the adrenal gland. The hSVCT2 mouse is expected to facilitate the search for drugs that inhibit damage by vitamin C oxidation products. PMID:17075057

Anatomy is important, but need not be destiny: novel uses of the thumb in aye-ayes compared to other lemurs.

PubMed

Pellis, Sergio M; Pellis, Vivien C

2012-06-01

Aye-ayes (Daubentonia madagascerensis) have highly specialized hands with long digits, especially the thin middle one (D3), which is used for extracting food, such as beetle larvae, under bark. Due to the elongation of their fingers, including the thumb, it is presumed that aye-ayes have a rather limited capacity for delicate manipulation of objects. However, studies have reported independent movement of digits D3 and D4, and one report noted a seemingly independent thumb (D1) movement in holding food. Sixteen captive adult aye-ayes were videotaped feeding on a diverse range of foods so as to document how the thumb is used during food holding. To determine if the patterns observed were unique to aye-ayes, 24 individuals from 9 other species of lemurs were also videotaped. Two patterns of thumb use idiosyncratic to aye-ayes and one other lemur, the sifaka (Propithecus verreauxi), were identified: (1) when holding a food item in one hand, the thumb was used to secure the food, with the other digits playing a secondary role; (2) when holding a food item with both hands, the thumbs once again took a predominant role in securing the food. In the majority of these cases, whether held by one or two thumbs, the thumbs curled around the item, but some descriptive evidence is provided that suggests that aye-ayes exaggerate the role of the thumbs by shifting the hold to the outer edge. The novel uses of the thumbs in aye-ayes demonstrate that brain mechanisms can sometimes override the behavioral (or motor) limitations imposed by the morphology of the body. Copyright © 2011 Elsevier B.V. All rights reserved.

Effects of mouse slant and desktop position on muscular and postural stresses, subject preference and performance in women aged 18-40 years.

PubMed

Gaudez, Clarisse; Cail, François

2016-11-01

This study compared muscular and postural stresses, performance and subject preference in women aged 18-40 years using a standard mouse, a vertical mouse and a slanted mouse in three different computer workstation positions. Four tasks were analysed: pointing, pointing-clicking, pointing-clicking-dragging and grasping-pointing the mouse after typing. Flexor digitorum superficialis (FDS) and extensor carpi radialis (ECR) activities were greater using the standard mouse compared to the vertical or slanted mouse. In all cases, the wrist position remained in the comfort zone recommended by standard ISO 11228-3. The vertical mouse was less comfortable and more difficult to use than the other two mice. FDS and ECR activities, shoulder abduction and wrist extension were greater when the mouse was placed next to the keyboard. Performance and subject preference were better with the unrestricted mouse positioning on the desktop. Grasping the mouse after typing was the task that caused the greatest stress. Practitioner Summary: In women, the slanted mouse and the unrestricted mouse positioning on the desktop provide a good blend of stresses, performance and preference. Unrestricted mouse positioning requires no keyboard, which is rare in practice. Placing the mouse in front of the keyboard, rather than next to it, reduced the physical load.

Vitamin E Supplementation Reduces Cellular Loss in the Brain of a Premature Aging Mouse Model.

PubMed

La Fata, G; van Vliet, N; Barnhoorn, S; Brandt, R M C; Etheve, S; Chenal, E; Grunenwald, C; Seifert, N; Weber, P; Hoeijmakers, J H J; Mohajeri, M H; Vermeij, W P

2017-01-01

Aging is a highly complex biological process driven by multiple factors. Its progression can partially be influenced by nutritional interventions. Vitamin E is a lipid-soluble anti-oxidant that is investigated as nutritional supplement for its ability to prevent or delay the onset of specific aging pathologies, including neurodegenerative disorders. We aimed here to investigate the effect of vitamin E during aging progression in a well characterized mouse model for premature aging. Xpg-/- animals received diets with low (~2.5 mg/kg feed), medium (75 mg/kg feed) or high (375 mg/kg feed) vitamin E concentration and their phenotype was monitored during aging progression. Vitamin E content was analyzed in the feed, for stability reasons, and in mouse plasma, brain, and liver, for effectiveness of the treatment. Subsequent age-related changes were monitored for improvement by increased vitamin E or worsening by depletion in both liver and nervous system, organs sensitive to oxidative stress. Mice supplemented with high levels of vitamin E showed a delayed onset of age-related body weight decline and appearance of tremors when compared to mice with a low dietary vitamin E intake. DNA damage resulting in liver abnormalities such as changes in polyploidy, was considerably prevented by elevated amounts of vitamin E. Additionally, immunohistochemical analyses revealed that high intake of vitamin E, when compared with low and medium levels of vitamin E in the diet, reduces the number of p53-positive cells throughout the brain, indicative of a lower number of cells dying due to DNA damage accumulated over time. Our data underline a neuroprotective role of vitamin E in the premature aging animal model used in this study, likely via a reduction of oxidative stress, and implies the importance of improved nutrition to sustain health.

A mouse model with age-dependent immune response and immune-tolerance for HBV infection.

PubMed

Yi, Xuerui; Yuan, Youcheng; Li, Na; Yi, Lu; Wang, Cuiling; Qi, Ying; Gong, Liang; Liu, Guangze; Kong, Xiangping

2018-02-01

Viral clearance of human HBV infection largely depends on the age of exposure. Thus, a mouse model with age-dependent immune response and immune-tolerance for HBV infection was established. HBVRag1 mice were generated by crossing Rag1 -/- mice with HBV-Tg mice. Following adoptive transfer of splenocytes adult (8-9 weeks old) and young (3 weeks old) HBVRag1 mice were named as HBVRag-ReA and HBVRag-ReY mice respectively. The biochemical parameters that were associated with viral load and immune function, as well as the histological evaluation of the liver tissues between the two mouse models were detected. The immune tolerance of HBVRag-ReY mice that were reconstituted at the early stages of life was evaluated by quantitative hepatitis B core antibody assay, adoptive transfer, and modulation of gut microbiota with the addition of antibiotics. HBVRag-ReA mice indicated apparent hepatocytes damage, clearance of HBsAg and production of HBsAb and HBcAb. HBVRag-ReY mice did not develop ALT elevation, and produced HBcAb and HBsAg. A higher number of hepatic CD8 + T and B cells promoted clearance of HBsAg in HBVRag-ReA mice following 30 days of lymphocyte transfer. In contrast to HBVRag-ReA mice, HBVRag-ReY mice exhibited higher levels of Th1/Th2 cytokines. HBVRag-ReY mice exhibited significantly higher (P < .01, approximately 10-fold) serum quantitative anti-HBc levels than HBV-Tg mice, which might be similar to the phase of immune clearance and immune tolerance in human HBV infection. Furthermore, the age-related tolerance in HBVRag-ReY mice that were sensitive to antibiotic treatment was different from that noted in HBV-Tg mice. GS-9620 could inhibit the production of HBsAg, whereas HBV vaccination could induce sustained seroconversion in HBVRag-ReY mice with low levels of HBsAg. The present study described a mouse model with age-dependent immunity and immune-tolerance for HBV infection in vivo, which may mimic chronic HBV infection in humans. Copyright © 2017

Relationships of microRNA expression in mouse lung with age and exposure to cigarette smoke and light

PubMed Central

Izzotti, Alberto; Calin, George A.; Steele, Vernon E.; Croce, Carlo M.; De Flora, Silvio

2009-01-01

MicroRNAs provide a formidable tool not only in cancer research but also to investigate physiological mechanisms and to assess the effect of environmental exposures in healthy tissues. Collectively, cigarette smoke and sunlight have been estimated to account for 40% of all human cancers, and not only smoke but also, surprisingly, UV light induced genomic and postgenomic alterations in mouse lung. Here we evaluated by microarray the expression of 484 microRNAs in the lungs of CD-1 mice, including newborns, postweanling males and females, and their dams, either untreated or exposed to environmental cigarette smoke and/or UV-containing light. The results obtained highlighted age-related variations in microRNA profiles, especially during the weanling period, due to perinatal stress and postnatal maturation of the lung. UV light alone did not affect pulmonary microRNAs, whereas smoke produced dramatic changes, mostly in the sense of down-regulation, reflecting both adaptive mechanisms and activation of pathways involved in the pathogenesis of pulmonary diseases. Both gender and age affected smoke-related microRNA dysregulation in mice. The data presented provide supporting evidence that microRNAs play a fundamental role in both physiological and pathological changes occurring in mouse lung.—Izzotti, A., Calin, G. A., Vernon E. St., Croce, G. M., De Flora, S. Relationships of microRNA expression in mouse lung with age and exposure to cigarette smoke and light. PMID:19465468

Developmental abnormalities and age-related neurodegeneration in a mouse model of Down syndrome

PubMed Central

Holtzman, David M.; Santucci, Daniela; Kilbridge, Joshua; Chua-Couzens, Jane; Fontana, David J.; Daniels, Scott E.; Johnson, Randolph M.; Chen, Karen; Sun, Yuling; Carlson, Elaine; Alleva, Enrico; Epstein, Charles J.; Mobley, William C.

1996-01-01

To study the pathogenesis of central nervous system abnormalities in Down syndrome (DS), we have analyzed a new genetic model of DS, the partial trisomy 16 (Ts65Dn) mouse. Ts65Dn mice have an extra copy of the distal aspect of mouse chromosome 16, a segment homologous to human chromosome 21 that contains much of the genetic material responsible for the DS phenotype. Ts65Dn mice show developmental delay during the postnatal period as well as abnormal behaviors in both young and adult animals that may be analogous to mental retardation. Though the Ts65Dn brain is normal on gross examination, there is age-related degeneration of septohippocampal cholinergic neurons and astrocytic hypertrophy, markers of the Alzheimer disease pathology that is present in elderly DS individuals. These findings suggest that Ts65Dn mice may be used to study certain developmental and degenerative abnormalities in the DS brain. PMID:8917591

Idiopathic paraproteinaemia. I. Studies in an animal model--the ageing C57BL/KaLwRij mouse.

PubMed Central

Radl, J; Hollander, C F; van den Berg, P; de Glopper, E

1978-01-01

A search for a suitable animal model for studies on idiopathic paraproteinaemia showed that an age-dependent increase in the appearance of homogeneous immunoglobulins in serum was common to all of the seven mouse strains investigated to date. The highest frequency was found in C57Bl/KaLwRij mice. Further investigations in this strain demonstrated that, except for some quantitative differences, most of the features of human and C57BL Mouse idiopathic paraproteinaemia were essentially the same. No clear-cut correlation was found between the idiopathic paraproteinaemia and, in the old C57B1 mice, a rather frequently occurring reticulum cell sarcoma B and amyloidosis. The mouse idiopathic paraproteinaemia can be regarded as an analogue of the human idiopathic paraproteinaemia and therefore as a suitable model for further experimental studies. PMID:367647

Sox10 Expressing Cells in the Lateral Wall of the Aged Mouse and Human Cochlea

PubMed Central

Hao, Xinping; Xing, Yazhi; Moore, Michael W.; Zhang, Jianning; Han, Demin; Schulte, Bradley A.; Dubno, Judy R.; Lang, Hainan

2014-01-01

Age-related hearing loss (presbycusis) is a common human disorder, affecting one in three Americans aged 60 and over. Previous studies have shown that presbyacusis is associated with a loss of non-sensory cells in the cochlear lateral wall. Sox10 is a transcription factor crucial to the development and maintenance of neural crest-derived cells including some non-sensory cell types in the cochlea. Mutations of the Sox10 gene are known to cause various combinations of hearing loss and pigmentation defects in humans. This study investigated the potential relationship between Sox10 gene expression and pathological changes in the cochlear lateral wall of aged CBA/CaJ mice and human temporal bones from older donors. Cochlear tissues prepared from young adult (1–3 month-old) and aged (2–2.5 year-old) mice, and human temporal bone donors were examined using quantitative immunohistochemical analysis and transmission electron microscopy. Cells expressing Sox10 were present in the stria vascularis, outer sulcus and spiral prominence in mouse and human cochleas. The Sox10+ cell types included marginal and intermediate cells and outer sulcus cells, including those that border the scala media and those extending into root processes (root cells) in the spiral ligament. Quantitative analysis of immunostaining revealed a significant decrease in the number of Sox10+ marginal cells and outer sulcus cells in aged mice. Electron microscopic evaluation revealed degenerative alterations in the surviving Sox10+ cells in aged mice. Strial marginal cells in human cochleas from donors aged 87 and older showed only weak immunostaining for Sox10. Decreases in Sox10 expression levels and a loss of Sox10+ cells in both mouse and human aged ears suggests an important role of Sox10 in the maintenance of structural and functional integrity of the lateral wall. A loss of Sox10+ cells may also be associated with a decline in the repair capabilities of non-sensory cells in the aged ear. PMID

Evidence of Highly Conserved β-Crystallin Disulfidome that Can be Mimicked by In Vitro Oxidation in Age-related Human Cataract and Glutathione Depleted Mouse Lens*

PubMed Central

Fan, Xingjun; Zhou, Sheng; Wang, Benlian; Hom, Grant; Guo, Minfei; Li, Binbin; Yang, Jing; Vaysburg, Dennis; Monnier, Vincent M

2015-01-01

Low glutathione levels are associated with crystallin oxidation in age-related nuclear cataract. To understand the role of cysteine residue oxidation, we used the novel approach of comparing human cataracts with glutathione-depleted LEGSKO mouse lenses for intra- versus intermolecular disulfide crosslinks using 2D-PAGE and proteomics, and then systematically identified in vivo and in vitro all disulfide forming sites using ICAT labeling method coupled with proteomics. Crystallins rich in intramolecular disulfides were abundant at young age in human and WT mouse lens but shifted to multimeric intermolecular disulfides at older age. The shift was ∼4x accelerated in LEGSKO lens. Most cysteine disulfides in β-crystallins (except βA4 in human) were highly conserved in mouse and human and could be generated by oxidation with H2O2, whereas γ-crystallin oxidation selectively affected γC23/42/79/80/154, γD42/33, and γS83/115/130 in human cataracts, and γB79/80/110, γD19/109, γF19/79, γE19, γS83/130, and γN26/128 in mouse. Analysis based on available crystal structure suggests that conformational changes are needed to expose Cys42, Cys79/80, Cys154 in γC; Cys42, Cys33 in γD, and Cys83, Cys115, and Cys130 in γS. In conclusion, the β-crystallin disulfidome is highly conserved in age-related nuclear cataract and LEGSKO mouse, and reproducible by in vitro oxidation, whereas some of the disulfide formation sites in γ-crystallins necessitate prior conformational changes. Overall, the LEGSKO mouse model is closely reminiscent of age-related nuclear cataract. PMID:26453637

Boosting ATM activity alleviates aging and extends lifespan in a mouse model of progeria

PubMed Central

Peng, Linyuan; Tang, Xiaolong; Meng, Fanbiao; Ao, Ying; Zhou, Mingyan; Wang, Ming; Cao, Xinyue; Qin, Baoming; Wang, Zimei; Zhou, Zhongjun; Wang, Guangming; Gao, Zhengliang; Xu, Jun

2018-01-01

DNA damage accumulates with age (Lombard et al., 2005). However, whether and how robust DNA repair machinery promotes longevity is elusive. Here, we demonstrate that ATM-centered DNA damage response (DDR) progressively declines with senescence and age, while low dose of chloroquine (CQ) activates ATM, promotes DNA damage clearance, rescues age-related metabolic shift, and prolongs replicative lifespan. Molecularly, ATM phosphorylates SIRT6 deacetylase and thus prevents MDM2-mediated ubiquitination and proteasomal degradation. Extra copies of Sirt6 extend lifespan in Atm-/- mice, with restored metabolic homeostasis. Moreover, the treatment with CQ remarkably extends lifespan of Caenorhabditis elegans, but not the ATM-1 mutants. In a progeria mouse model with low DNA repair capacity, long-term administration of CQ ameliorates premature aging features and extends lifespan. Thus, our data highlights a pro-longevity role of ATM, for the first time establishing direct causal links between robust DNA repair machinery and longevity, and providing therapeutic strategy for progeria and age-related metabolic diseases. PMID:29717979

Novel gene function revealed by mouse mutagenesis screens for models of age-related disease.

PubMed

Potter, Paul K; Bowl, Michael R; Jeyarajan, Prashanthini; Wisby, Laura; Blease, Andrew; Goldsworthy, Michelle E; Simon, Michelle M; Greenaway, Simon; Michel, Vincent; Barnard, Alun; Aguilar, Carlos; Agnew, Thomas; Banks, Gareth; Blake, Andrew; Chessum, Lauren; Dorning, Joanne; Falcone, Sara; Goosey, Laurence; Harris, Shelley; Haynes, Andy; Heise, Ines; Hillier, Rosie; Hough, Tertius; Hoslin, Angela; Hutchison, Marie; King, Ruairidh; Kumar, Saumya; Lad, Heena V; Law, Gemma; MacLaren, Robert E; Morse, Susan; Nicol, Thomas; Parker, Andrew; Pickford, Karen; Sethi, Siddharth; Starbuck, Becky; Stelma, Femke; Cheeseman, Michael; Cross, Sally H; Foster, Russell G; Jackson, Ian J; Peirson, Stuart N; Thakker, Rajesh V; Vincent, Tonia; Scudamore, Cheryl; Wells, Sara; El-Amraoui, Aziz; Petit, Christine; Acevedo-Arozena, Abraham; Nolan, Patrick M; Cox, Roger; Mallon, Anne-Marie; Brown, Steve D M

2016-08-18

Determining the genetic bases of age-related disease remains a major challenge requiring a spectrum of approaches from human and clinical genetics to the utilization of model organism studies. Here we report a large-scale genetic screen in mice employing a phenotype-driven discovery platform to identify mutations resulting in age-related disease, both late-onset and progressive. We have utilized N-ethyl-N-nitrosourea mutagenesis to generate pedigrees of mutagenized mice that were subject to recurrent screens for mutant phenotypes as the mice aged. In total, we identify 105 distinct mutant lines from 157 pedigrees analysed, out of which 27 are late-onset phenotypes across a range of physiological systems. Using whole-genome sequencing we uncover the underlying genes for 44 of these mutant phenotypes, including 12 late-onset phenotypes. These genes reveal a number of novel pathways involved with age-related disease. We illustrate our findings by the recovery and characterization of a novel mouse model of age-related hearing loss.

Novel gene function revealed by mouse mutagenesis screens for models of age-related disease

PubMed Central

Potter, Paul K.; Bowl, Michael R.; Jeyarajan, Prashanthini; Wisby, Laura; Blease, Andrew; Goldsworthy, Michelle E.; Simon, Michelle M.; Greenaway, Simon; Michel, Vincent; Barnard, Alun; Aguilar, Carlos; Agnew, Thomas; Banks, Gareth; Blake, Andrew; Chessum, Lauren; Dorning, Joanne; Falcone, Sara; Goosey, Laurence; Harris, Shelley; Haynes, Andy; Heise, Ines; Hillier, Rosie; Hough, Tertius; Hoslin, Angela; Hutchison, Marie; King, Ruairidh; Kumar, Saumya; Lad, Heena V.; Law, Gemma; MacLaren, Robert E.; Morse, Susan; Nicol, Thomas; Parker, Andrew; Pickford, Karen; Sethi, Siddharth; Starbuck, Becky; Stelma, Femke; Cheeseman, Michael; Cross, Sally H.; Foster, Russell G.; Jackson, Ian J.; Peirson, Stuart N.; Thakker, Rajesh V.; Vincent, Tonia; Scudamore, Cheryl; Wells, Sara; El-Amraoui, Aziz; Petit, Christine; Acevedo-Arozena, Abraham; Nolan, Patrick M.; Cox, Roger; Mallon, Anne-Marie; Brown, Steve D. M.

2016-01-01

Determining the genetic bases of age-related disease remains a major challenge requiring a spectrum of approaches from human and clinical genetics to the utilization of model organism studies. Here we report a large-scale genetic screen in mice employing a phenotype-driven discovery platform to identify mutations resulting in age-related disease, both late-onset and progressive. We have utilized N-ethyl-N-nitrosourea mutagenesis to generate pedigrees of mutagenized mice that were subject to recurrent screens for mutant phenotypes as the mice aged. In total, we identify 105 distinct mutant lines from 157 pedigrees analysed, out of which 27 are late-onset phenotypes across a range of physiological systems. Using whole-genome sequencing we uncover the underlying genes for 44 of these mutant phenotypes, including 12 late-onset phenotypes. These genes reveal a number of novel pathways involved with age-related disease. We illustrate our findings by the recovery and characterization of a novel mouse model of age-related hearing loss. PMID:27534441

Evidence for the possible occurrence of Grave's disease in a blue-eyed black lemur (Eulemur flavifrons).

PubMed

Quintard, Benoît; Giorgiadis, Marine; Feirrera, Xavier; Lefaux, Brice; Schohn, Christophe; Lemberger, Karin

2018-03-01

The blue-eyed black lemur (Eulemur flavifrons) is classified by the International Union for Conservation of Nature (IUCN) as critically endangered. A 23-year-old male housed at Mulhouse Zoo presented with lethargy, polyphagia, alopecia, and chronic weight loss. Clinical examination suggested an endocrine pathology such as hyperthyroidism. Secondary examinations included cervical ultrasound, thyroid biopsy, and scintigraphy. The latter revealed elevated thyroid activity. Blood analysis was performed to measure the level of anti-receptor thyroid-stimulating hormone antibodies, which allowed us to test the autoimmune hypothesis. The high level of antibodies together with levels of thyroid-stimulating hormone and the scintigraphy images led to the diagnosis of Grave's disease. Carbimazole treatment followed by thyroidectomy resulted in a quick weight gain and general improvement in health status. The following breeding season, the treated individual sired an offspring. To the authors' knowledge, this is the first report of likely Grave's disease in a non-human primate.

Systemic Mesenchymal Stromal Cell Transplantation Prevents Functional Bone Loss in a Mouse Model of Age-Related Osteoporosis.

PubMed

Kiernan, Jeffrey; Hu, Sally; Grynpas, Marc D; Davies, John E; Stanford, William L

2016-05-01

Age-related osteoporosis is driven by defects in the tissue-resident mesenchymal stromal cells (MSCs), a heterogeneous population of musculoskeletal progenitors that includes skeletal stem cells. MSC decline leads to reduced bone formation, causing loss of bone volume and the breakdown of bony microarchitecture crucial to trabecular strength. Furthermore, the low-turnover state precipitated by MSC loss leads to low-quality bone that is unable to perform remodeling-mediated maintenance--replacing old damaged bone with new healthy tissue. Using minimally expanded exogenous MSCs injected systemically into a mouse model of human age-related osteoporosis, we show long-term engraftment and markedly increased bone formation. This led to improved bone quality and turnover and, importantly, sustained microarchitectural competence. These data establish proof of concept that MSC transplantation may be used to prevent or treat human age-related osteoporosis. This study shows that a single dose of minimally expanded mesenchymal stromal cells (MSCs) injected systemically into a mouse model of human age-related osteoporosis display long-term engraftment and prevent the decline in bone formation, bone quality, and microarchitectural competence. This work adds to a growing body of evidence suggesting that the decline of MSCs associated with age-related osteoporosis is a major transformative event in the progression of the disease. Furthermore, it establishes proof of concept that MSC transplantation may be a viable therapeutic strategy to treat or prevent human age-related osteoporosis. ©AlphaMed Press.

Systemic Mesenchymal Stromal Cell Transplantation Prevents Functional Bone Loss in a Mouse Model of Age-Related Osteoporosis

PubMed Central

Kiernan, Jeffrey; Hu, Sally; Grynpas, Marc D.

2016-01-01

Age-related osteoporosis is driven by defects in the tissue-resident mesenchymal stromal cells (MSCs), a heterogeneous population of musculoskeletal progenitors that includes skeletal stem cells. MSC decline leads to reduced bone formation, causing loss of bone volume and the breakdown of bony microarchitecture crucial to trabecular strength. Furthermore, the low-turnover state precipitated by MSC loss leads to low-quality bone that is unable to perform remodeling-mediated maintenance—replacing old damaged bone with new healthy tissue. Using minimally expanded exogenous MSCs injected systemically into a mouse model of human age-related osteoporosis, we show long-term engraftment and markedly increased bone formation. This led to improved bone quality and turnover and, importantly, sustained microarchitectural competence. These data establish proof of concept that MSC transplantation may be used to prevent or treat human age-related osteoporosis. Significance This study shows that a single dose of minimally expanded mesenchymal stromal cells (MSCs) injected systemically into a mouse model of human age-related osteoporosis display long-term engraftment and prevent the decline in bone formation, bone quality, and microarchitectural competence. This work adds to a growing body of evidence suggesting that the decline of MSCs associated with age-related osteoporosis is a major transformative event in the progression of the disease. Furthermore, it establishes proof of concept that MSC transplantation may be a viable therapeutic strategy to treat or prevent human age-related osteoporosis. PMID:26987353

Effects of Isometric Scaling on Vertical Jumping Performance

PubMed Central

Bobbert, Maarten F.

2013-01-01

Jump height, defined as vertical displacement in the airborne phase, depends on vertical takeoff velocity. For centuries, researchers have speculated on how jump height is affected by body size and many have adhered to what has come to be known as Borelli’s law, which states that jump height does not depend on body size per se. The underlying assumption is that the amount of work produced per kg body mass during the push-off is independent of size. However, if a big body is isometrically downscaled to a small body, the latter requires higher joint angular velocities to achieve a given takeoff velocity and work production will be more impaired by the force-velocity relationship of muscle. In the present study, the effects of pure isometric scaling on vertical jumping performance were investigated using a biologically realistic model of the human musculoskeletal system. The input of the model, muscle stimulation over time, was optimized using jump height as criterion. It was found that when the human model was miniaturized to the size of a mouse lemur, with a mass of about one-thousandth that of a human, jump height dropped from 40 cm to only 6 cm, mainly because of the force-velocity relationship. In reality, mouse lemurs achieve jump heights of about 33 cm. By implication, the unfavourable effects of the small body size of mouse lemurs on jumping performance must be counteracted by favourable effects of morphological and physiological adaptations. The same holds true for other small jumping animals. The simulations for the first time expose and explain the sheer magnitude of the isolated effects of isometric downscaling on jumping performance, to be counteracted by morphological and physiological adaptations. PMID:23936494

Reproductive Resilience to Food Shortage in a Small Heterothermic Primate

PubMed Central

Perret, Martine; Henry, Pierre-Yves

2012-01-01

The massive energetic costs entailed by reproduction in most mammalian females may increase the vulnerability of reproductive success to food shortage. Unexpected events of unfavorable climatic conditions are expected to rise in frequency and intensity as climate changes. The extent to which physiological flexibility allows organisms to maintain reproductive output constant despite energetic bottlenecks has been poorly investigated. In mammals, reproductive resilience is predicted to be maximal during early stages of reproduction, due to the moderate energetic costs of ovulation and gestation relative to lactation. We experimentally tested the consequences of chronic-moderate and short-acute food shortages on the reproductive output of a small seasonally breeding primate, the grey mouse lemur (Microcebus murinus) under thermo-neutral conditions. These two food treatments were respectively designed to simulate the energetic constraints imposed by a lean year (40% caloric restriction over eight months) or by a sudden, severe climatic event occurring shortly before reproduction (80% caloric restriction over a month). Grey mouse lemurs evolved under the harsh, unpredictable climate of the dry forest of Madagascar and should thus display great potential for physiological adjustments to energetic bottlenecks. We assessed the resilience of the early stages of reproduction (mating success, fertility, and gestation) to these contrasted food treatments, and on the later stages (lactation and offspring growth) in response to the chronic food shortage only. Food deprived mouse lemurs managed to maintain constant most reproductive parameters, including oestrus timing, estrogenization level at oestrus, mating success, litter size, and litter mass as well as their overall number of surviving offspring at weaning. However, offspring growth was delayed in food restricted mothers. These results suggest that heterothermic, fattening-prone mammals display important reproductive

Reproductive resilience to food shortage in a small heterothermic primate.

PubMed

Canale, Cindy I; Huchard, Elise; Perret, Martine; Henry, Pierre-Yves

2012-01-01

The massive energetic costs entailed by reproduction in most mammalian females may increase the vulnerability of reproductive success to food shortage. Unexpected events of unfavorable climatic conditions are expected to rise in frequency and intensity as climate changes. The extent to which physiological flexibility allows organisms to maintain reproductive output constant despite energetic bottlenecks has been poorly investigated. In mammals, reproductive resilience is predicted to be maximal during early stages of reproduction, due to the moderate energetic costs of ovulation and gestation relative to lactation. We experimentally tested the consequences of chronic-moderate and short-acute food shortages on the reproductive output of a small seasonally breeding primate, the grey mouse lemur (Microcebus murinus) under thermo-neutral conditions. These two food treatments were respectively designed to simulate the energetic constraints imposed by a lean year (40% caloric restriction over eight months) or by a sudden, severe climatic event occurring shortly before reproduction (80% caloric restriction over a month). Grey mouse lemurs evolved under the harsh, unpredictable climate of the dry forest of Madagascar and should thus display great potential for physiological adjustments to energetic bottlenecks. We assessed the resilience of the early stages of reproduction (mating success, fertility, and gestation) to these contrasted food treatments, and on the later stages (lactation and offspring growth) in response to the chronic food shortage only. Food deprived mouse lemurs managed to maintain constant most reproductive parameters, including oestrus timing, estrogenization level at oestrus, mating success, litter size, and litter mass as well as their overall number of surviving offspring at weaning. However, offspring growth was delayed in food restricted mothers. These results suggest that heterothermic, fattening-prone mammals display important reproductive

Expression of Ambra1 in mouse brain during physiological and Alzheimer type aging.

PubMed

Sepe, Sara; Nardacci, Roberta; Fanelli, Francesca; Rosso, Pamela; Bernardi, Cinzia; Cecconi, Francesco; Mastroberardino, Pier G; Piacentini, Mauro; Moreno, Sandra

2014-01-01

Autophagy is a major protein degradation pathway, essential for stress-induced and constitutive protein turnover. In nervous tissue, autophagy is constitutively active and crucial to neuronal survival. The efficiency of the autophagic pathway reportedly undergoes age-related decline, and autophagy defects are observed in neurodegenerative diseases. Since Ambra1 plays a fundamental role in regulating the autophagic process in developing nervous tissue, we investigated the expression of this protein in mature mouse brain and during physiological and Alzheimer type aging. The present study accomplished the first complete map of Ambra1 protein distribution in the various brain areas, and highlights differential expression in neuronal/glial cell populations. Differences in Ambra1 content are possibly related to specific neuronal features and properties, particularly concerning susceptibility to neurodegeneration. Furthermore, the analysis of Ambra1 expression in physiological and pathological brain aging supports important, though conflicting, functions of autophagy in neurodegenerative processes. Thus, novel therapeutic approaches, based on autophagy modulation, should also take into account the age-dependent roles of this mechanism in establishing, promoting, or counteracting neurodegeneration. Copyright © 2014 Elsevier Inc. All rights reserved.

Changes in glomerular parietal epithelial cells in mouse kidneys with advanced age

PubMed Central

Roeder, Sebastian S.; Stefanska, Ania; Eng, Diana G.; Kaverina, Natalya; Sunseri, Maria W.; McNicholas, Bairbre A.; Rabinovitch, Peter; Engel, Felix B.; Daniel, Christoph; Amann, Kerstin; Lichtnekert, Julia; Pippin, Jeffrey W.

2015-01-01

Kidney aging is accompanied by characteristic changes in the glomerulus, but little is known about the effect of aging on glomerular parietal epithelial cells (PECs), nor if the characteristic glomerular changes in humans and rats also occur in very old mice. Accordingly, a descriptive analysis was undertaken in 27-mo-old C57B6 mice, considered advanced age. PEC density was significantly lower in older mice compared with young mice (aged 3 mo), and the decrease was more pronounced in juxtamedullary glomeruli compared with outer cortical glomeruli. In addition to segmental and global glomerulosclerosis in older mice, staining for matrix proteins collagen type IV and heparan sulfate proteoglycan were markedly increased in Bowman's capsules of older mouse glomeruli, consistent with increased extracellular matrix production by PECs. De novo staining for CD44, a marker of activated and profibrotic PECs, was significantly increased in aged glomeruli. CD44 staining was more pronounced in the juxtamedullary region and colocalized with phosphorylated ERK. Additionally, a subset of aged PECs de novo expressed the epithelial-to-mesenchymal transition markers α-smooth muscle and vimentin, with no changes in epithelial-to-mesenchymal transition markers E-cadherin and β-catenin. The mural cell markers neural/glial antigen 2, PDGF receptor-β, and CD146 as well as Notch 3 were also substantially increased in aged PECs. These data show that mice can be used to better understand the aging kidney and that PECs undergo substantial changes, especially in juxtamedullary glomeruli, that may participate in the overall decline in glomerular structure and function with advancing age. PMID:26017974

In utero bisphenol A exposure disrupts germ cell nest breakdown and reduces fertility with age in the mouse

DOE Office of Scientific and Technical Information (OSTI.GOV)

Wang, Wei, E-mail: weiwang2@illinois.edu; Hafner, Katlyn S., E-mail: katlynhafner@gmail.com; Flaws, Jodi A., E-mail: jflaws@illinois.edu

Bisphenol A (BPA) is a known reproductive toxicant in rodents. However, the effects of in utero BPA exposure on early ovarian development and the consequences of such exposure on female reproduction in later reproductive life are unclear. Thus, we determined the effects of in utero BPA exposure during a critical developmental window on germ cell nest breakdown, a process required for establishment of the finite primordial follicle pool, and on female reproduction. Pregnant FVB mice (F0) were orally dosed daily with tocopherol-striped corn oil (vehicle), diethylstilbestrol (DES; 0.05 μg/kg, positive control), or BPA (0.5, 20, and 50 μg/kg) from gestationalmore » day 11 until birth. Ovarian morphology and gene expression profiles then were examined in F1 female offspring on postnatal day (PND) 4 and estrous cyclicity was examined daily after weaning for 30 days. F1 females were also subjected to breeding studies with untreated males at three to nine months. The results indicate that BPA inhibits germ cell nest breakdown via altering expression of selected apoptotic factors. BPA also significantly advances the age of first estrus, shortens the time that the females remain in estrus, and increases the time that the females remain in metestrus and diestrus compared to controls. Further, F1 females exposed to low doses of BPA exhibit various fertility problems and have a significantly higher percentage of dead pups compared to controls. These results indicate that in utero exposure to low doses of BPA during a critical ovarian developmental window interferes with early ovarian development and reduces fertility with age. - Highlights: • In utero BPA exposure inhibits germ cell nest breakdown in female mouse offspring. • In utero BPA exposure alters expression of apoptosis regulators in the ovaries of mouse offspring. • In utero BPA exposure advances first estrus age and alters cyclicity in mouse offspring. • In utero BPA exposure causes various fertility

Boosting ATM activity alleviates aging and extends lifespan in a mouse model of progeria.

PubMed

Qian, Minxian; Liu, Zuojun; Peng, Linyuan; Tang, Xiaolong; Meng, Fanbiao; Ao, Ying; Zhou, Mingyan; Wang, Ming; Cao, Xinyue; Qin, Baoming; Wang, Zimei; Zhou, Zhongjun; Wang, Guangming; Gao, Zhengliang; Xu, Jun; Liu, Baohua

2018-05-02

DNA damage accumulates with age (Lombard et al., 2005). However, whether and how robust DNA repair machinery promotes longevity is elusive. Here, we demonstrate that ATM-centered DNA damage response (DDR) progressively declines with senescence and age, while low dose of chloroquine (CQ) activates ATM, promotes DNA damage clearance, rescues age-related metabolic shift, and prolongs replicative lifespan. Molecularly, ATM phosphorylates SIRT6 deacetylase and thus prevents MDM2-mediated ubiquitination and proteasomal degradation. Extra copies of Sirt6 extend lifespan in Atm-/- mice, with restored metabolic homeostasis. Moreover, the treatment with CQ remarkably extends lifespan of Caenorhabditis elegans , but not the ATM-1 mutants. In a progeria mouse model with low DNA repair capacity, long-term administration of CQ ameliorates premature aging features and extends lifespan. Thus, our data highlights a pro-longevity role of ATM, for the first time establishing direct causal links between robust DNA repair machinery and longevity, and providing therapeutic strategy for progeria and age-related metabolic diseases. © 2018, Qian et al.

Age-related behavioral phenotype of an astrocytic monoamine oxidase-B transgenic mouse model of Parkinson's disease.

PubMed

Lieu, Christopher A; Chinta, Shankar J; Rane, Anand; Andersen, Julie K

2013-01-01

We have previously shown that increases in astrocytic monoamine oxidase-B (MAO-B) expression, mimicking that which occurs with aging and in neurodegenerative disease, in a doxycycline (dox)-inducible transgenic mouse model evokes neuropathological similarities to what is observed in the human parkinsonian brain. Additional behavioral and neuropathological studies could provide further validation for its usage as a model for Parkinson's disease (PD). In the present study, we utilized a battery of behavioral tests to evaluate age-related phenotype in this model. In the open field test, we found that dox-induction impaired motor ability with decreases in movement and ambulatory function as well as diminished stereotypical, repetitive movement episodes in both young and old mice. Older mice also showed decreased motor performance in the pole test when compared to younger mice. Furthermore, dox-induced older mice displayed severe hindlimb clasping and the most significant loss of dopamine (DA) in the striatum when compared to young and non-induced animals. Additionally, increased MAO-B activity significantly correlated with decreased expression of striatal DA. The results of our study further confirms that the dox-inducible astrocytic MAO-B transgenic mouse displays similar age-related behavioral and neuropathological features to other models of PD, and could serve as a useful tool to study PD pathophysiology and for the evaluation of therapeutic interventions.

Surgical and medical management for fractures of the second through fifth metacarpals in a red ruffed lemur (Varecia rubra).

PubMed

Cerveny, Shannon N S; Harper, Justin; Voges, Andra; Coke, Rob L

2013-03-01

A 21-yr-old female red ruffed lemur (Varecia rubra) was presented with swelling and disuse of the right manus. Severely displaced fractures of metacarpals II-V were diagnosed radiographically. The fractures were surgically stabilized with intramedullary Kirschner wires attached externally with an acrylic external fixator and a bone plate on the dorsal aspect of metacarpal III. The fractures of metacarpals II-V were predominantly healed on radiographs obtained 12 wk after surgery. However, diffuse disuse osteopenia and phalangeal contracture were present, with possible osteomyelitis. An exercise regimen of the affected hand was initiated due to the incomplete extension of the phalanges. After 4 wk of therapy, the extension of the phalanges had improved and the fractures appeared radiographically to be nearly completely healed. Although metacarpal fractures are common in nonhuman primates, they are reported infrequently in the literature.

Anti-aging effect of adipose-derived stem cells in a mouse model of skin aging induced by D-galactose.

PubMed

Zhang, Shengchang; Dong, Ziqing; Peng, Zhangsong; Lu, Feng

2014-01-01

Glycation products accumulate during aging of slowly renewing tissue, including skin, and are suggested as an important mechanism underlying the skin aging process. Adipose-derived cells are widely used in the clinic to treat ischemic diseases and enhance wound healing. Interestingly, adipose-derived stem cells (ASCs) are also effective in anti-aging therapy, although the mechanism underlying their effects remains unknown. The purpose of the present study was to examine the anti-aging effect of ASCs in a D-galactose-induced aging animal model and to clarify the underlying mechanism. Six-week-old nude mice were subcutaneously injected with D-gal daily for 8 weeks. Two weeks after completion of treatment, mice were randomized to receive subcutaneous injections of 106 green fluorescent protein (GFP)-expressing ASCs, aminoguanidine (AG) or phosphate-buffered saline (PBS). Control mice received no treatment. We examined tissue histology and determined the activity of senescence-associated molecular markers such as superoxide dismutase (SOD) and malondialdehyde (MDA). Transplanted ASCs were detectable for 14 days and their GFP signal disappeared at day 28 after injection. ASCs inhibited advanced glycation end product (AGE) levels in our animal model as well as increased the SOD level and decreased the MDA level, all of which act to reverse the aging phenotype in a similar way to AG, an inhibitor of AGE formation. Furthermore, ASCs released angiogenic factors in vivo such as vascular endothelial growth factor, suggesting a skin trophic effect. These results demonstrate that ASCs may contribute to the regeneration of skin during aging. In addition, the data shows that ASCs provide a functional benefit by glycation suppression, antioxidation, and trophic effects in a mouse model of aging.

Age- and Hypertension-Associated Protein Aggregates in Mouse Heart Have Similar Proteomic Profiles.

PubMed

Ayyadevara, Srinivas; Mercanti, Federico; Wang, Xianwei; Mackintosh, Samuel G; Tackett, Alan J; Prayaga, Sastry V S; Romeo, Francesco; Shmookler Reis, Robert J; Mehta, Jawahar L

2016-05-01

Neurodegenerative diseases are largely defined by protein aggregates in affected tissues. Aggregates contain some shared components as well as proteins thought to be specific for each disease. Aggregation has not previously been reported in the normal, aging heart or the hypertensive heart. Detergent-insoluble protein aggregates were isolated from mouse heart and characterized on 2-dimensional gels. Their levels increased markedly and significantly with aging and after sustained angiotensin II-induced hypertension. Of the aggregate components identified by high-resolution proteomics, half changed in abundance with age (392/787) or with sustained hypertension (459/824), whereas 30% (273/901) changed concordantly in both, each P<0.05. One fifth of these proteins were previously associated with age-progressive neurodegenerative or cardiovascular diseases, or both (eg, ApoE, ApoJ, ApoAIV, clusterin, complement C3, and others involved in stress-response and protein-homeostasis pathways). Because fibrosis is a characteristic of both aged and hypertensive hearts, we posited that aging of fibroblasts may contribute to the aggregates observed in cardiac tissue. Indeed, as cardiac myofibroblasts "senesced" (approached their replicative limit) in vitro, they accrued aggregates with many of the same constituent proteins observed in vivo during natural aging or sustained hypertension. In summary, we have shown for the first time that compact (detergent-insoluble) protein aggregates accumulate during natural aging, chronic hypertension, and in vitro myofibroblast senescence, sharing many common proteins. Thus, aggregates that arise from disparate causes (aging, hypertension, and replicative senescence) may have common underlying mechanisms of accrual. © 2016 American Heart Association, Inc.

Age-Related Behavioral Phenotype of an Astrocytic Monoamine Oxidase-B Transgenic Mouse Model of Parkinson’s Disease

PubMed Central

Lieu, Christopher A.; Chinta, Shankar J.; Rane, Anand; Andersen, Julie K.

2013-01-01

We have previously shown that increases in astrocytic monoamine oxidase-B (MAO-B) expression, mimicking that which occurs with aging and in neurodegenerative disease, in a doxycycline (dox)-inducible transgenic mouse model evokes neuropathological similarities to what is observed in the human parkinsonian brain. Additional behavioral and neuropathological studies could provide further validation for its usage as a model for Parkinson’s disease (PD). In the present study, we utilized a battery of behavioral tests to evaluate age-related phenotype in this model. In the open field test, we found that dox-induction impaired motor ability with decreases in movement and ambulatory function as well as diminished stereotypical, repetitive movement episodes in both young and old mice. Older mice also showed decreased motor performance in the pole test when compared to younger mice. Furthermore, dox-induced older mice displayed severe hindlimb clasping and the most significant loss of dopamine (DA) in the striatum when compared to young and non-induced animals. Additionally, increased MAO-B activity significantly correlated with decreased expression of striatal DA. The results of our study further confirms that the dox-inducible astrocytic MAO-B transgenic mouse displays similar age-related behavioral and neuropathological features to other models of PD, and could serve as a useful tool to study PD pathophysiology and for the evaluation of therapeutic interventions. PMID:23326597

Relationships of microRNA expression in mouse lung with age and exposure to cigarette smoke and light.

PubMed

Izzotti, Alberto; Calin, George A; Steele, Vernon E; Croce, Carlo M; De Flora, Silvio

2009-09-01

MicroRNAs provide a formidable tool not only in cancer research but also to investigate physiological mechanisms and to assess the effect of environmental exposures in healthy tissues. Collectively, cigarette smoke and sunlight have been estimated to account for 40% of all human cancers, and not only smoke but also, surprisingly, UV light induced genomic and postgenomic alterations in mouse lung. Here we evaluated by microarray the expression of 484 microRNAs in the lungs of CD-1 mice, including newborns, postweanling males and females, and their dams, either untreated or exposed to environmental cigarette smoke and/or UV-containing light. The results obtained highlighted age-related variations in microRNA profiles, especially during the weanling period, due to perinatal stress and postnatal maturation of the lung. UV light alone did not affect pulmonary microRNAs, whereas smoke produced dramatic changes, mostly in the sense of down-regulation, reflecting both adaptive mechanisms and activation of pathways involved in the pathogenesis of pulmonary diseases. Both gender and age affected smoke-related microRNA dysregulation in mice. The data presented provide supporting evidence that microRNAs play a fundamental role in both physiological and pathological changes occurring in mouse lung.

Convenience polyandry or convenience polygyny? Costly sex under female control in a promiscuous primate.

PubMed

Huchard, Elise; Canale, Cindy I; Le Gros, Chloé; Perret, Martine; Henry, Pierre-Yves; Kappeler, Peter M

2012-04-07

Classic sex roles depict females as choosy, but polyandry is widespread. Empirical attempts to understand the evolution of polyandry have often focused on its adaptive value to females, whereas 'convenience polyandry' might simply decrease the costs of sexual harassment. We tested whether constraint-free female strategies favour promiscuity over mating selectivity through an original experimental design. We investigated variation in mating behaviour in response to a reversible alteration of sexual dimorphism in body mass in the grey mouse lemur, a small primate where female brief sexual receptivity allows quantifying polyandry. We manipulated body condition in captive females, predicting that convenience polyandry would increase when females are weaker than males, thus less likely to resist their solicitations. Our results rather support the alternative hypothesis of 'adaptive polyandry': females in better condition are more polyandrous. Furthermore, we reveal that multiple mating incurs significant energetic costs, which are strikingly symmetrical between the sexes. Our study shows that mouse lemur females exert tight control over mating and actively seek multiple mates. The benefits of remating are nevertheless not offset by its costs in low-condition females, suggesting that polyandry is a flexible strategy yielding moderate fitness benefits in this small mammal.

Production of lymphocyte-activating factors by mouse macrophages during aging and under the effect of short peptides.

PubMed

Gumen, A V; Kozinets, I A; Shanin, S N; Malinin, V V; Rybakina, E G

2006-09-01

Age-specific characteristics of production of lymphocyte-activating factor by mouse peritoneal macrophages and modulation of this production by short synthetic peptides (Vilon, Epithalon, and Cortagen) were studied. The production of lymphocyte-activating factors by macrophages stimulated with lipopolysaccharides in vitro was lower in old animals. The opposite modulating effects of short peptides on the production of lymphocyte-activating factors by resident and lipopolysaccharide-stimulated macrophages in young and old mice were demonstrated for the first time. This is a possible mechanism of immune system dysfunction during aging, which opens new vistas for its correction with short synthetic peptides.

l-tyrosine induces melanocyte differentiation in novel pink-eyed dilution castaneus mouse mutant showing age-related pigmentation.

PubMed

Hirobe, Tomohisa; Ishikawa, Akira

2015-12-01

The mouse pink-eyed dilution (oculocutaneous albinism II; p/Oca2(p)) locus is known to control tyrosinase activity, melanin content, and melanosome development in melanocytes. Pink-eyed dilution castaneus (p(cas)/Oca2(p-cas)) is a novel mutant allele on mouse chromosome 7 that arose spontaneously in Indonesian wild mice, Mus musculus castaneus. Mice homozygous for Oca2(p-cas) usually exhibit pink eyes and beige-colored coat on nonagouti C57BL/6 (B6) background. Recently, a novel spontaneous mutation occurred in the progeny between this mutant and B6 mice. The eyes of this novel mutant progressively become black from pink and the coat becomes dark gray from beige with aging. The aim of this study is to clarify whatever differences exist in melanocyte proliferation and differentiation between the ordinary (pink-eyed) and novel (black-eyed) mutant using serum-free primary culture system. The characteristics of melanocyte proliferation and differentiation were investigated by serum-free primary culture system using melanocyte-proliferation medium (MDMD). The proliferation of melanoblasts in MDMD did not differ between the two mice. However, when the epidermal cell suspensions were cultured with MDMD supplemented with l-tyrosine (Tyr), the differentiation of black-eyed melanocytes was greatly induced in a concentration-dependent manner compared with pink-eyed melanocytes. Immunocytochemistry demonstrated that the expression of tyrosinase and tyrosinase-related protein-1 (Tyrp1) was greatly induced or stimulated both in pink-eyed and black-eyed melanocytes, whereas the expression of microphthalmia-associated transcription factor (Mitf) was stimulated only in black-eyed melanocytes. These results suggest that the age-related coat darkening in black-eyed mutant may be caused by the increased ability of melanocyte differentiation dependent on l-Tyr through the upregulation of tyrosinase, Tyrp1, and Mitf. This mutant mouse may be useful for animal model to clarify the

Mouse Tmem135 mutation reveals a mechanism involving mitochondrial dynamics that leads to age-dependent retinal pathologies

PubMed Central

Lee, Wei-Hua; Higuchi, Hitoshi; Ikeda, Sakae; Macke, Erica L; Takimoto, Tetsuya; Pattnaik, Bikash R; Liu, Che; Chu, Li-Fang; Siepka, Sandra M; Krentz, Kathleen J; Rubinstein, C Dustin; Kalejta, Robert F; Thomson, James A; Mullins, Robert F; Takahashi, Joseph S; Pinto, Lawrence H; Ikeda, Akihiro

2016-01-01

While the aging process is central to the pathogenesis of age-dependent diseases, it is poorly understood at the molecular level. We identified a mouse mutant with accelerated aging in the retina as well as pathologies observed in age-dependent retinal diseases, suggesting that the responsible gene regulates retinal aging, and its impairment results in age-dependent disease. We determined that a mutation in the transmembrane 135 (Tmem135) is responsible for these phenotypes. We observed localization of TMEM135 on mitochondria, and imbalance of mitochondrial fission and fusion in mutant Tmem135 as well as Tmem135 overexpressing cells, indicating that TMEM135 is involved in the regulation of mitochondrial dynamics. Additionally, mutant retina showed higher sensitivity to oxidative stress. These results suggest that the regulation of mitochondrial dynamics through TMEM135 is critical for protection from environmental stress and controlling the progression of retinal aging. Our study identified TMEM135 as a critical link between aging and age-dependent diseases. DOI: http://dx.doi.org/10.7554/eLife.19264.001 PMID:27863209

Aging, Breast Cancer and the Mouse Model

DTIC Science & Technology

2005-05-01

architecture and function of the of normal human cells in culture ( Hayflick , 1965). This limit surrounding tissue and stimulate (or inhibit) the... LIMITATION 18. NUMBER 19a. NAME OF RESPONSIBLE PERSON OF ABSTRACT OF PAGES USAMRMC a. REPORT b. ABSTRACT c. THIS PAGE 19b. TELEPHONE NUMBER (include area U...mammary cancers in the mouse and that these tumors have strikingly similar histology. Nonetheless, several limitations exists to this model system and

Age-Related Alterations in the Metabolic Profile in the Hippocampus of the Senescence-Accelerated Mouse Prone 8: A Spontaneous Alzheimer's Disease Mouse Model

PubMed Central

Wang, Hualong; Lian, Kaoqi; Han, Bing; Wang, Yanyong; Kuo, Sheng-Han; Geng, Yuan; Qiang, Jing; Sun, Meiyu; Wang, Mingwei

2015-01-01

Alzheimer's disease (AD), the most common age-dependent neurodegenerative disorder, produces a progressive decline in cognitive function. The metabolic mechanism of AD has emerged in recent years. In this study, we used multivariate analyses of gas chromatography-mass spectrometry measurements to determine that learning and retention-related metabolic profiles are altered during aging in the hippocampus of the senescence-accelerated mouse prone 8 (SAMP8). Alterations in 17 metabolites were detected in mature and aged mice compared to young mice (13 decreased and 4 increased metabolites), including metabolites related to dysfunctional lipid metabolism (significantly increased cholesterol, oleic acid, and phosphoglyceride levels), decreased amino acid (alanine, serine, glycine, aspartic acid, glutamate, and gamma-aminobutyric acid), and energy-related metabolite levels (malic acid, butanedioic acid, fumaric acid, and citric acid), and other altered metabolites (increased N-acetyl-aspartic acid and decreased pyroglutamic acid, urea, and lactic acid) in the hippocampus. All of these alterations indicated that the metabolic mechanisms of age-related cognitive impairment in SAMP8 mice were related to multiple pathways and networks. Lipid metabolism, especially cholesterol metabolism, appears to play a distinct role in the hippocampus in AD. PMID:24284365

Conditional Deletion of the Pten Gene in the Mouse Prostate Induces Prostatic Intraepithelial Neoplasms at Early Ages but a Slow Progression to Prostate Tumors

PubMed Central

Zhu, Chunfang; Lee, Suk Hyung; Ye, Ding-Wei; Luong, Richard; Sun, Zijie

2013-01-01

The PTEN tumor suppressor gene is frequently inactivated in human prostate cancer. Using Osr1 (odd skipped related 1)-Cre mice, we generated a novel conditional Pten knockout mouse strain, PtenLoxP:Osr1-Cre. Conditional biallelic and monoallelic Pten knockout mice were viable. Deletion of Pten expression was detected in the prostate of PtenLoxP/LoxP:Osr1-Cre mice as early as 2 weeks of age. Intriguingly, PtenLoxP/LoxP:Osr1-Cre mice develop high-grade prostatic intraepithelial neoplasms (PINs) with high penetrance as early as one-month of age, and locally invasive prostatic tumors after 12-months of age. PtenLoxP/+:Osr1-Cre mice show only mild oncogenic changes after 8-weeks of age. Castration of PtenLoxP/LoxP:Osr1-Cre mice shows no significant regression of prostate tumors, although a shift of androgen receptor (AR) staining from the nuclei to cytoplasm is observed in Pten null tumor cells of castrated mice. Enhanced Akt activity is observed in Pten null tumor cells of castrated PtenLoxP/LoxP:Osr1-Cre. This study provides a novel mouse model that can be used to investigate a primary role of Pten in initiating oncogenic transformation in the prostate and to examine other genetic and epigenetic changes that are required for tumor progression in the mouse prostate. PMID:23308230

Mitochondrial base excision repair in mouse synaptosomes during normal aging and in a model of Alzheimer’s disease

PubMed Central

Gredilla, Ricardo; Weissman, Lior; Yang, Jenq-Lin; Bohr, Vilhelm A.; Stevnsner, Tinna

2010-01-01

Brain aging is associated with synaptic decline and cognitive impairment. Increased levels of oxidative DNA base damage and accumulation of mitochondrial DNA (mtDNA) mutations or deletions lead to mitochondrial dysfunction, playing an important role in the aging process and the pathogenesis of neurodegenerative diseases such as Alzheimer’s disease (AD). In mitochondria, base excision repair (BER) is the main DNA repair pathway for base modifications such as deamination and oxidation, and constitutes an important mechanism to avoid accumulation of mtDNA mutations. Synaptic function is highly dependent on mitochondria, and in the current study we have investigated BER in synaptosomes of mouse brain during normal aging and in an AD model. Synaptosomes are isolated synapses in membranous structures produced by subcellular fractionation of brain tissue. They include the whole presynaptic terminal as well as portions of the postsynaptic terminal. Synaptosomes contain the molecular machinery necessary for uptake, storage, and release of neurotransmitters, including synaptic vesicles and mitochondria. BER activities were measured in synaptosomal fractions from young and old mice and from pre-symptomatic and symptomatic AD mice harboring mutated APP, Tau and PS1 (3xTgAD). During normal aging, a reduction in the BER capacity was observed in the synaptosomal fraction, which was associated with a decrease in the level of BER proteins. However, we did not observe changes between the synaptosomal BER activities of pre-symptomatic and symptomatic AD mice. Our findings suggest that the age-related reduction in BER capacity in the synaptosomal fraction might contribute to mitochondrial and synaptic dysfunction during aging. The development of AD-like pathology in the 3xTgAD mouse model was, however, not associated with deficiencies of the BER mechanisms in the synaptosomal fraction when the whole brain was analyzed. PMID:20708822

Mouse allergen exposure, wheeze and atopy in the first seven years of life

PubMed Central

Phipatanakul, W.; Celedón, J. C.; Hoffman, E. B.; Abdulkerim, H.; Ryan, L. M.; Gold, D. R.

2008-01-01

Background Little is known about mouse allergen exposure in home environments and the development of wheezing, asthma and atopy in childhood. Objective To examine the relation between mouse allergen exposure and wheezing, atopy, and asthma in the first 7 years of life. Methods Prospective study of 498 children with parental history of allergy or asthma followed from birth to age 7 years, with longitudinal questionnaire ascertainment of reported mouse exposure and dust sample mouse urinary protein allergen levels measured at age 2–3 months. Results Parental report of mouse exposure in the first year of life was associated with increased risk of transient wheeze and wheezing in early life. Current report of mouse exposure was also significantly associated with current wheeze throughout the first 7 years of life in the longitudinal analysis (P = 0.03 for overall relation of current mouse to current wheeze). However, early life mouse exposure did not predict asthma, eczema or allergic rhinitis at age 7 years. Exposure to detectable levels of mouse urinary protein in house dust samples collected at age 2–3 months was associated with a twofold increase in the odds of atopy (sensitization to >=1 allergen) at school age (95% confidence interval for odds ratio = 1.1–3.7; P = 0.03 in a multivariate analysis. Conclusions Among children with parental history of asthma or allergies, current mouse exposure is associated with increased risk of wheeze during the first 7 years of life. Early mouse exposure was associated with early wheeze and atopy later in life. PMID:18616677

The Changing Sensory and Sympathetic Innervation of the Young, Adult and Aging Mouse Femur.

PubMed

Chartier, Stephane R; Mitchell, Stefanie A T; Majuta, Lisa A; Mantyh, Patrick W

2018-02-10

Although bone is continually being remodeled and ultimately declines with aging, little is known whether similar changes occur in the sensory and sympathetic nerve fibers that innervate bone. Here, immunohistochemistry and confocal microscopy were used to examine changes in the sensory and sympathetic nerve fibers that innervate the young (10 days post-partum), adult (3 months) and aging (24 months) C57Bl/6 mouse femur. In all three ages examined, the periosteum was the most densely innervated bone compartment. With aging, the total number of sensory and sympathetic nerve fibers clearly declines as the cambium layer of the periosteum dramatically thins. Yet even in the aging femur, there remains a dense sensory and sympathetic innervation of the periosteum. In cortical bone, sensory and sympathetic nerve fibers are largely confined to vascularized Haversian canals and while there is no significant decline in the density of sensory fibers, there was a 75% reduction in sympathetic nerve fibers in the aging vs. adult cortical bone. In contrast, in the bone marrow the overall density/unit area of both sensory and sympathetic nerve fibers appeared to remain largely unchanged across the lifespan. The preferential preservation of sensory nerve fibers suggests that even as bone itself undergoes a marked decline with age, the nociceptors that detect injury and signal skeletal pain remain relatively intact. Copyright © 2018 The Author(s). Published by Elsevier Ltd.. All rights reserved.

Melatonin improves the fertilization ability of post-ovulatory aged mouse oocytes by stabilizing ovastacin and Juno to promote sperm binding and fusion.

PubMed

Dai, Xiaoxin; Lu, Yajuan; Zhang, Mianqun; Miao, Yilong; Zhou, Changyin; Cui, Zhaokang; Xiong, Bo

2017-03-01

What are the underlying mechanisms of the decline in the fertilization ability of post-ovulatory aged oocytes? Melatonin improves the fertilization ability of post-ovulatory aged oocytes by reducing aging-induced reactive oxygen species (ROS) levels and inhibiting apoptosis and by maintaining the levels and localization of the fertilization proteins, ovastacin and Juno. Following ovulation, the quality of mammalian metaphase II oocytes irreversibly deteriorates over time with a concomitant loss of fertilization ability. Melatonin has been found to prevent post-ovulatory oocyte aging and extend the window for optimal fertilization in mice. Mouse oocytes were randomly assigned to three groups and aged in vitro for 0, 6, 12 and 24 h, respectively. Increasing concentrations of melatonin (10-9 M, 10-7 M, 10-5 M and 10-3 M) were added to the 24 h aging group. Sperm binding assays, in-vitro fertilization, immunofluorescent staining and western blotting were performed to investigate key regulators and events during fertilization of post-ovulatory aged mouse oocytes. We found that the actin cap which promotes a cortical granule (CG) free domain is disrupted with a re-distribution of CGs in the subcortex of aged oocytes. Ovastacin, a CG metalloendoprotease, is mis-located and prematurely exocytosed in aged oocytes with subsequent cleavage of the zona pellucida protein ZP2. This disrupts the sperm recognition domain and dramatically reduces the number of sperm binding to the zona pellucida. The abundance of Juno, the sperm receptor on the oocyte membrane, also is reduced in aged oocytes. Exposure of aged oocytes to melatonin significantly elevates in-vitro fertilization rates potentially by rescuing the above age-associated defects of fertilization, and reducing ROS and inhibiting apoptosis. N/A. We explored the mechanisms of the decline in fertilization ability decline in aged mouse oocytes, in vitro but not in vivo. Our findings may contribute to the development a more

Regional differences in the morphological and functional effects of aging on cerebral basement membranes and perivascular drainage of amyloid-β from the mouse brain.

PubMed

Hawkes, Cheryl A; Gatherer, Maureen; Sharp, Matthew M; Dorr, Adrienne; Yuen, Ho Ming; Kalaria, Rajesh; Weller, Roy O; Carare, Roxana O

2013-04-01

Development of cerebral amyloid angiopathy (CAA) and Alzheimer's disease (AD) is associated with failure of elimination of amyloid-β (Aβ) from the brain along perivascular basement membranes that form the pathways for drainage of interstitial fluid and solutes from the brain. In transgenic APP mouse models of AD, the severity of cerebral amyloid angiopathy is greater in the cerebral cortex and hippocampus, intermediate in the thalamus, and least in the striatum. In this study we test the hypothesis that age-related regional variation in (1) vascular basement membranes and (2) perivascular drainage of Aβ contribute to the different regional patterns of CAA in the mouse brain. Quantitative electron microscopy of the brains of 2-, 7-, and 23-month-old mice revealed significant age-related thickening of capillary basement membranes in cerebral cortex, hippocampus, and thalamus, but not in the striatum. Results from Western blotting and immunocytochemistry experiments showed a significant reduction in collagen IV in the cortex and hippocampus with age and a reduction in laminin and nidogen 2 in the cortex and striatum. Injection of soluble Aβ into the hippocampus or thalamus showed an age-related reduction in perivascular drainage from the hippocampus but not from the thalamus. The results of the study suggest that changes in vascular basement membranes and perivascular drainage with age differ between brain regions, in the mouse, in a manner that may help to explain the differential deposition of Aβ in the brain in AD and may facilitate development of improved therapeutic strategies to remove Aβ from the brain in AD. © 2013 The Authors Aging Cell © 2013 Blackwell Publishing Ltd/Anatomical Society of Great Britain and Ireland.

Modification of a Limbed Robot to Favor Climbing

NASA Technical Reports Server (NTRS)

Okon, Avi; Kennedy, Brett; Garrett, Michael; Magnone, Lee

2006-01-01

The figure shows the LEMUR IIb, which is a modified version of the LEMUR II the second generation of the Limbed Excursion Mechanical Utility Robot (LEMUR). Except as described below, the LEMUR IIb hardware is mostly the same as that of the LEMUR II. The IIb and II versions differ in their kinematic configurations and characteristics associated with their kinematic configurations. The differences are such that relative to the LEMUR II, the LEMUR IIb is simpler and is better suited to climbing on inclined surfaces. The first-generation LEMUR, now denoted the LEMUR I, was described in Six-Legged Experimental Robot (NPO-20897), NASA Tech Briefs, Vol. 25, No. 12 (December 2001), page 58. The LEMUR II was described in Second-Generation Six-Limbed Experimental Robot (NPO-35140) NASA Tech Briefs, Vol. 28, No. 11 (November 2004), page 55. To recapitulate: the LEMUR I and LEMUR II were six-legged or sixlimbed robots for demonstrating robotic capabilities for assembly, maintenance, and inspection. They were designed to be capable of walking autonomously along a truss structure toward a mechanical assembly at a prescribed location. They were equipped with stereoscopic video cameras and image-data-processing circuitry for navigation and mechanical operations. They were also equipped with wireless modems, through which they could be commanded remotely. Upon arrival at a mechanical assembly, the LEMUR I would perform simple mechanical operations by use of one or both of its front legs (or in the case of the LEMUR II, any of its limbs could be used to perform mechanical operations). Either LEMUR could also transmit images to a host computer. The differences between the LEMUR IIb and the LEMUR II are the following: Whereas the LEMUR II had six limbs, the LEMUR IIb has four limbs. This change has reduced both the complexity and mass of the legs and of the overall robot. Whereas each limb of the LEMUR II had four degrees of freedom (DOFs), each limb of the LEMUR IIb has three DOFs

Shortened estrous cycle length, increased FSH levels, FSH variance, oocyte spindle aberrations, and early declining fertility in aging senescence-accelerated mouse prone-8 (SAMP8) mice: concomitant characteristics of human midlife female reproductive aging.

PubMed

Bernstein, Lori R; Mackenzie, Amelia C L; Kraemer, Duane C; Morley, John E; Farr, Susan; Chaffin, Charles L; Merchenthaler, István

2014-06-01

Women experience a series of specific transitions in their reproductive function with age. Shortening of the menstrual cycle begins in the mid to late 30s and is regarded as the first sign of reproductive aging. Other early changes include elevation and increased variance of serum FSH levels, increased incidences of oocyte spindle aberrations and aneuploidy, and declining fertility. The goal of this study was to investigate whether the mouse strain senescence-accelerated mouse-prone-8 (SAMP8) is a suitable model for the study of these midlife reproductive aging characteristics. Midlife SAMP8 mice aged 6.5-7.85 months (midlife SAMP8) exhibited shortened estrous cycles compared with SAMP8 mice aged 2-3 months (young SAMP8, P = .0040). Midlife SAMP8 mice had high FSH levels compared with young SAMP8 mice, and mice with a single day of high FSH exhibited statistically elevated FSH throughout the cycle, ranging from 1.8- to 3.6-fold elevation on the days of proestrus, estrus, metestrus, and diestrus (P < .05). Midlife SAMP8 mice displayed more variance in FSH than young SAMP8 mice (P = .01). Midlife SAMP8 ovulated fewer oocytes (P = .0155). SAMP8 oocytes stained with fluorescently labeled antitubulin antibodies and scored in fluorescence microscopy exhibited increased incidence of meiotic spindle aberrations with age, from 2/126 (1.59%) in young SAMP8 to 38/139 (27.3%) in midlife SAMP8 (17.2-fold increase, P < .0001). Finally, SAMP8 exhibited declining fertility from 8.9 pups/litter in young SAMP8 to 3.5 pups/litter in midlife SAMP8 mice (P < .0001). The age at which these changes occur is younger than for most mouse strains, and their simultaneous occurrence within a single strain has not been described previously. We propose that SAMP8 mice are a model of midlife human female reproductive aging.

Mouse forepaw lumbrical muscles are resistant to age-related declines in force production.

PubMed

Russell, Katelyn A; Ng, Rainer; Faulkner, John A; Claflin, Dennis R; Mendias, Christopher L

2015-05-01

A progressive loss of skeletal muscle mass and force generating capacity occurs with aging. Mice are commonly used in the study of aging-associated changes in muscle size and strength, with most models of aging demonstrating 15-35% reductions in muscle mass, cross-sectional area (CSA), maximum isometric force production (Po) and specific force (sPo), which is Po/CSA. The lumbrical muscle of the mouse forepaw is exceptionally small, with corresponding short diffusion distances that make it ideal for in vitro pharmacological studies and measurements of contractile properties. However, the aging-associated changes in lumbrical function have not previously been reported. To address this, we tested the hypothesis that compared to adult (12month old) mice, the forepaw lumbrical muscles of old (30month old) mice exhibit aging-related declines in size and force production similar to those observed in larger limb muscles. We found that the forepaw lumbricals were composed exclusively of fibers with type II myosin heavy chain isoforms, and that the muscles accumulated connective tissue with aging. There were no differences in the number of fibers per whole-muscle cross-section or in muscle fiber CSA. The whole muscle CSA in old mice was increased by 17%, but the total CSA of all muscle fibers in a whole-muscle cross-section was not different. No difference in Po was observed, and while sPo normalized to total muscle CSA was decreased in old mice by 22%, normalizing Po by the total muscle fiber CSA resulted in no difference in sPo. Combined, these results indicate that forepaw lumbrical muscles from 30month old mice are largely protected from the aging-associated declines in size and force production that are typically observed in larger limb muscles. Copyright © 2015 Elsevier Inc. All rights reserved.

White spotting variant mouse as an experimental model for ovarian aging and menopausal biology.

PubMed

Smith, Elizabeth R; Yeasky, Toni; Wei, Jain Qin; Miki, Roberto A; Cai, Kathy Q; Smedberg, Jennifer L; Yang, Wan-Lin; Xu, Xiang-Xi

2012-05-01

Menopause is a unique phenomenon in modern women, as most mammalian species possess a reproductive period comparable with their life span. Menopause is caused by the depletion of germ cell-containing ovarian follicles and in laboratory studies is usually modeled in animals in which the ovarian function is removed through ovariectomy or chemical poisoning of the germ cells. Our objective was to explore and characterize the white spotting variant (Wv) mice that have reduced ovarian germ cell abundance, a result of a point mutation in the c-kit gene that decreases kinase activity, as a genetic model for use in menopause studies. Physiological and morphological features associated with menopause were determined in female Wv/Wv mice compared with age-matched wildtype controls. Immunohistochemistry was used to evaluate the presence and number of follicles in paraffin-embedded ovaries. Bone density and body composition were evaluated using the PIXImus x-ray densitometer, and lipids, calcium, and hormone levels were determined in serum using antigen-specific enzyme immunoassays. Heart and body weight were measured, and cardiac function was evaluated using transthoracic echocardiography. The ovaries of the Wv/Wv females have a greatly reduced number of normal germ cells at birth compared with wildtype mice. The remaining follicles are depleted by around 2 months, and the ovaries develop benign epithelial lesions that resemble morphological changes that occur during ovarian aging, whereas a normal mouse ovary has numerous follicles at all stages of development and retains some follicles even in advanced age. Wv mice have elevated plasma gonadotropins and reduced estrogen and progesterone levels, a significant reduction in bone mass density, and elevated serum cholesterol and lipoprotein levels. Moreover, the Wv female mice have enlarged hearts and reduced cardiac function. The reduction of c-kit activity in Wv mice leads to a substantially diminished follicular endowment in

Convenience polyandry or convenience polygyny? Costly sex under female control in a promiscuous primate

PubMed Central

Huchard, Elise; Canale, Cindy I.; Le Gros, Chloé; Perret, Martine; Henry, Pierre-Yves; Kappeler, Peter M.

2012-01-01

Classic sex roles depict females as choosy, but polyandry is widespread. Empirical attempts to understand the evolution of polyandry have often focused on its adaptive value to females, whereas ‘convenience polyandry’ might simply decrease the costs of sexual harassment. We tested whether constraint-free female strategies favour promiscuity over mating selectivity through an original experimental design. We investigated variation in mating behaviour in response to a reversible alteration of sexual dimorphism in body mass in the grey mouse lemur, a small primate where female brief sexual receptivity allows quantifying polyandry. We manipulated body condition in captive females, predicting that convenience polyandry would increase when females are weaker than males, thus less likely to resist their solicitations. Our results rather support the alternative hypothesis of ‘adaptive polyandry’: females in better condition are more polyandrous. Furthermore, we reveal that multiple mating incurs significant energetic costs, which are strikingly symmetrical between the sexes. Our study shows that mouse lemur females exert tight control over mating and actively seek multiple mates. The benefits of remating are nevertheless not offset by its costs in low-condition females, suggesting that polyandry is a flexible strategy yielding moderate fitness benefits in this small mammal. PMID:21976684

Targeted myocardial delivery of GDF11 gene rejuvenates the aged mouse heart and enhances myocardial regeneration after ischemia-reperfusion injury.

PubMed

Du, Guo-Qing; Shao, Zheng-Bo; Wu, Jie; Yin, Wen-Juan; Li, Shu-Hong; Wu, Jun; Weisel, Richard D; Tian, Jia-Wei; Li, Ren-Ke

2017-01-01

Ischemic cardiac injury is the main contributor to heart failure, and the regenerative capacity of intrinsic stem cells plays an important role in tissue repair after injury. However, stem cells in aged individuals have reduced regenerative potential and aged tissues lack the capacity to renew. Growth differentiation factor 11 (GDF11), from the activin-transforming growth factor β superfamily, has been shown to promote stem cell activity and rejuvenation. We carried out non-invasive targeted delivery of the GDF11 gene to the heart using ultrasound-targeted microbubble destruction (UTMD) and cationic microbubble (CMB) to investigate the ability of GDF11 to rejuvenate the aged heart and improve tissue regeneration after injury. Young (3 months) and old (21 months) mice were used to evaluate the expression of GDF11 mRNA in the myocardium at baseline and after ischemia/reperfusion (I/R) and myocardial infarction. GDF11 expression decreased with age and following myocardial injury. UTMD-mediated delivery of the GDF11 plasmid to the aged heart after I/R injury effectively and selectively increased GDF11 expression in the heart, and improved cardiac function and reduced infarct size. Over-expression of GDF11 decreased senescence markers, p16 and p53, as well as the number of p16 + cells in old mouse hearts. Furthermore, increased proliferation of cardiac stem cell antigen 1 (Sca-1 + ) cells and increased homing of endothelial progenitor cells and angiogenesis in old ischemic hearts occurred after GDF11 over-expression. Repetitive targeted delivery of the GDF11 gene via UTMD can rejuvenate the aged mouse heart and protect it from I/R injury.

Anti-skin-aging effect of epigallocatechin gallate by regulating epidermal growth factor receptor pathway on aging mouse model induced by d-Galactose.

PubMed

Chen, Jiming; Li, Yifan; Zhu, Qiangqiang; Li, Tong; Lu, Hao; Wei, Nan; Huang, Yewei; Shi, Ruoyu; Ma, Xiao; Wang, Xuanjun; Sheng, Jun

2017-06-01

Epigallocatechin gallate(EGCG) is a monomer separated from tea catechins, as an well-known antioxidant, which helps fight wrinkles and rejuvenate skin cells. In this study, we investigated the anti-aging effect of EGCG, and to clarify underlying mechanism of skin aging in a d-galactose-induced aging mouse model. Forty-five male mice were divided into 5 groups and treated with different dose of EGCG, Vitamin C (VitC) to mice as a positive control. All groups except vehicle were established aging model induced by d-galactose (200mg/kg/day) that was subcutaneously injected to mice for 8 weeks. Two weeks after injection of d-galactose, EGCG and Vit C groups were simultaneously administered once a day by subcutaneously inject after 5h for injecting d-galactose. The results show that EGCG can be absorbed by the skin. Overall, the conditions of the skin of EGCG-treatment groups were improved, the whole structure of skin were better than control groups, and the levels of oxidative stress and the expression of relate with EGFR proteins were significantly higher than control group after EGCG treatment. All these findings suggest that EGCG can resist skin senility effectively. And the EGFR with relate of downstream proteins are implicated in the skin aging. Copyright © 2017. Published by Elsevier B.V.

Effects of aging and sensory loss on glial cells in mouse visual and auditory cortices

PubMed Central

Tremblay, Marie-Ève; Zettel, Martha L.; Ison, James R.; Allen, Paul D.; Majewska, Ania K.

2011-01-01

Normal aging is often accompanied by a progressive loss of receptor sensitivity in hearing and vision, whose consequences on cellular function in cortical sensory areas have remained largely unknown. By examining the primary auditory (A1) and visual (V1) cortices in two inbred strains of mice undergoing either age-related loss of audition (C57BL/6J) or vision (CBA/CaJ), we were able to describe cellular and subcellular changes that were associated with normal aging (occurring in A1 and V1 of both strains) or specifically with age-related sensory loss (only in A1 of C57BL/6J or V1 of CBA/CaJ), using immunocytochemical electron microscopy and light microscopy. While the changes were subtle in neurons, glial cells and especially microglia were transformed in aged animals. Microglia became more numerous and irregularly distributed, displayed more variable cell body and process morphologies, occupied smaller territories, and accumulated phagocytic inclusions that often displayed ultrastructural features of synaptic elements. Additionally, evidence of myelination defects were observed, and aged oligodendrocytes became more numerous and were more often encountered in contiguous pairs. Most of these effects were profoundly exacerbated by age-related sensory loss. Together, our results suggest that the age-related alteration of glial cells in sensory cortical areas can be accelerated by activity-driven central mechanisms that result from an age-related loss of peripheral sensitivity. In light of our observations, these age-related changes in sensory function should be considered when investigating cellular, cortical and behavioral functions throughout the lifespan in these commonly used C57BL/6J and CBA/CaJ mouse models. PMID:22223464

Development of a novel pink-eyed dilution mouse model showing progressive darkening of the eyes and coat hair with aging

PubMed Central

ISHIKAWA, Akira; SUGIYAMA, Makoto; HONDO, Eiichi; KINOSHITA, Keiji; YAMAGISHI, Yuki

2015-01-01

Oca2p-cas (oculocutaneous albinism II; pink-eyed dilution castaneus) is a coat color mutant gene on mouse chromosome 7 that arose spontaneously in wild Mus musculus castaneus mice. Mice homozygous for Oca2p-cas usually exhibit pink eyes and gray coat hair on the non-agouti genetic background, and this ordinary phenotype remains unchanged throughout life. During breeding of a mixed strain carrying this gene on the C57BL/6J background, we discovered a novel spontaneous mutation that causes darkening of the eyes and coat hair with aging. In this study, we developed a novel mouse model showing this unique phenotype. Gross observations revealed that the pink eyes and gray coat hair of the novel mutant young mice became progressively darker in color by approximately 3 months after birth. Light and transmission-electron microscopic observations revealed a marked increase in melanin pigmentation of coat hair shafts and choroid of the eye in the novel mice compared to that in the ordinary mice. Sequence analysis of Oca2p-cas revealed a 4.1-kb deletion involving exons 15 and 16 of its wild-type gene. However, there was no sequence difference between the two types of mutant mice. Mating experiments suggested that the novel mutant phenotype was not inherited in a simple fashion, due to incomplete penetrance. The novel spontaneous mutant mouse is the first example of progressive hair darkening animals and is an essential animal model for understanding of the regulation mechanisms of melanin biosynthesis with aging. PMID:25739360

Development of a novel pink-eyed dilution mouse model showing progressive darkening of the eyes and coat hair with aging.

PubMed

Ishikawa, Akira; Sugiyama, Makoto; Hondo, Eiichi; Kinoshita, Keiji; Yamagishi, Yuki

2015-01-01

Oca2(p-cas) (oculocutaneous albinism II; pink-eyed dilution castaneus) is a coat color mutant gene on mouse chromosome 7 that arose spontaneously in wild Mus musculus castaneus mice. Mice homozygous for Oca2(p-cas) usually exhibit pink eyes and gray coat hair on the non-agouti genetic background, and this ordinary phenotype remains unchanged throughout life. During breeding of a mixed strain carrying this gene on the C57BL/6J background, we discovered a novel spontaneous mutation that causes darkening of the eyes and coat hair with aging. In this study, we developed a novel mouse model showing this unique phenotype. Gross observations revealed that the pink eyes and gray coat hair of the novel mutant young mice became progressively darker in color by approximately 3 months after birth. Light and transmission-electron microscopic observations revealed a marked increase in melanin pigmentation of coat hair shafts and choroid of the eye in the novel mice compared to that in the ordinary mice. Sequence analysis of Oca2(p-cas) revealed a 4.1-kb deletion involving exons 15 and 16 of its wild-type gene. However, there was no sequence difference between the two types of mutant mice. Mating experiments suggested that the novel mutant phenotype was not inherited in a simple fashion, due to incomplete penetrance. The novel spontaneous mutant mouse is the first example of progressive hair darkening animals and is an essential animal model for understanding of the regulation mechanisms of melanin biosynthesis with aging.

Age-associated increase in aneuploidy and changes in gene expression in mouse eggs

PubMed Central

Pan, Hua; Ma, Pengpeng; Zhu, Wenting; Schultz, Richard M.

2008-01-01

An increase in the incidence of aneuploidy is well documented with increasing maternal age, in particular in human females. Remarkably, little is known regarding the underlying molecular basis for the age-associated increase in aneuploidy, which is a major source of decreased fertility in humans. Using mouse as a model system we find that eggs obtained from old mice (60–70 weeks of age) display a six-fold increase in the incidence of hyperploidy as assessed by chromosome spreads. Expression profiling of transcripts in oocytes and eggs obtained from young and old mice reveals that ~5% of the transcripts are differentially expressed in oocytes obtained from old females when compared to oocytes obtained from young females (6–12 weeks of age) and that this fraction increases to ~33% in eggs. The latter finding indicates that the normal pattern of degradation of maternal mRNAs that occurs during oocyte maturation is dramatically altered in eggs obtained from old mice and could therefore be a contributing source to the decline in fertility. Analysis of the differentially expressed transcripts also indicated that the strength of the spindle assembly checkpoint is weakened and that higher errors of microtubule-kinetochore interactions constitute part of molecular basis for the ageassociated increase in aneuploidy in females. Last, BRCA1 expression is reduced in oocytes obtained from old females and RNAi-mediated reduction of BRCA1 in oocytes obtained from young females results in perturbing spindle formation and chromosome congression following maturation. PMID:18342300

Peripheral administration of antisense oligonucleotides targeting the amyloid-β protein precursor reverses AβPP and LRP-1 overexpression in the aged SAMP8 mouse brain.

PubMed

Erickson, Michelle A; Niehoff, Michael L; Farr, Susan A; Morley, John E; Dillman, Lucy A; Lynch, Kristin M; Banks, William A

2012-01-01

The senescence accelerated mouse-prone 8 (SAMP8) mouse model of Alzheimer's disease has a natural mutation leading to age-related increases in the amyloid-β protein precursor (AβPP) and amyloid-β (Aβ) in the brain, memory impairment, and deficits in Aβ removal from the brain. Previous studies show that centrally administered antisense oligonucleotide directed against AβPP can decrease AβPP expression and Aβ production in the brains of aged SAMP8 mice, and improve memory. The same antisense crosses the blood-brain barrier and reverses memory deficits when injected intravenously. Here, we give 6 μg of AβPP or control antisense 3 times over 2 week intervals to 12 month old SAMP8 mice. Object recognition test was done 48 hours later, followed by removal of whole brains for immunoblot analysis of AβPP, low-density lipoprotein-related protein-1 (LRP-1), p-glycoprotein (Pgp), receptor for advanced glycation endproducts (RAGE), or ELISA of soluble Aβ(40). Our results show that AβPP antisense completely reverses a 30% age-associated increase in AβPP signal (p < 0.05 versus untreated 4 month old SAMP8). Soluble Aβ(40) increased with age, but was not reversed by antisense. LRP-1 large and small subunits increased significantly with age (147.7%, p < 0.01 and 123.7%, p < 0.05 respectively), and AβPP antisense completely reversed these increases (p < 0.05). Pgp and RAGE were not significantly altered with age or antisense. Antisense also caused improvements in memory (p < 0.001). Together, these data support the therapeutic potential of AβPP antisense and show a unique association between AβPP and LRP-1 expression in the SAMP8 mouse.

Lifelong obesity in a polygenic mouse model prevents age- and diet-induced glucose intolerance- obesity is no road to late-onset diabetes in mice.

PubMed

Renne, Ulla; Langhammer, Martina; Brenmoehl, Julia; Walz, Christina; Zeissler, Anja; Tuchscherer, Armin; Piechotta, Marion; Wiesner, Rudolf J; Bielohuby, Maximilian; Hoeflich, Andreas

2013-01-01

Visceral obesity holds a central position in the concept of the metabolic syndrome characterized by glucose intolerance in humans. However, until now it is unclear if obesity by itself is responsible for the development of glucose intolerance. We have used a novel polygenic mouse model characterized by genetically fixed obesity (DU6) and addressed age- and high fat diet-dependent glucose tolerance. Phenotype selection over 146 generations increased body weight by about 2.7-fold in male 12-week DU6 mice (P<0.0001) if compared to unselected controls (Fzt:DU). Absolute epididymal fat mass was particularly responsive to weight selection and increased by more than 5-fold (P<0.0001) in male DU6 mice. At an age of 6 weeks DU6 mice consumed about twice as much food if compared to unselected controls (P<0.001). Absolute food consumption was higher at all time points measured in DU6 mice than in Fzt:DU mice. Between 6 and 12 weeks of age, absolute food intake was reduced by 15% in DU6 mice (P<0.001) but not in Fzt:DU mice. In both mouse lines feeding of the high fat diet elevated body mass if compared to the control diet (P<0.05). In contrast to controls, DU6 mice did not display high fat diet-induced increases of epididymal and renal fat. Control mice progressively developed glucose intolerance with advancing age and even more in response to the high fat diet. In contrast, obese DU6 mice did neither develop a glucose intolerant phenotype with progressive age nor when challenged with a high fat diet. Our results from a polygenic mouse model demonstrate that genetically pre-determined and life-long obesity is no precondition of glucose intolerance later in life.

Effects of aging and sensory loss on glial cells in mouse visual and auditory cortices.

PubMed

Tremblay, Marie-Ève; Zettel, Martha L; Ison, James R; Allen, Paul D; Majewska, Ania K

2012-04-01

Normal aging is often accompanied by a progressive loss of receptor sensitivity in hearing and vision, whose consequences on cellular function in cortical sensory areas have remained largely unknown. By examining the primary auditory (A1) and visual (V1) cortices in two inbred strains of mice undergoing either age-related loss of audition (C57BL/6J) or vision (CBA/CaJ), we were able to describe cellular and subcellular changes that were associated with normal aging (occurring in A1 and V1 of both strains) or specifically with age-related sensory loss (only in A1 of C57BL/6J or V1 of CBA/CaJ), using immunocytochemical electron microscopy and light microscopy. While the changes were subtle in neurons, glial cells and especially microglia were transformed in aged animals. Microglia became more numerous and irregularly distributed, displayed more variable cell body and process morphologies, occupied smaller territories, and accumulated phagocytic inclusions that often displayed ultrastructural features of synaptic elements. Additionally, evidence of myelination defects were observed, and aged oligodendrocytes became more numerous and were more often encountered in contiguous pairs. Most of these effects were profoundly exacerbated by age-related sensory loss. Together, our results suggest that the age-related alteration of glial cells in sensory cortical areas can be accelerated by activity-driven central mechanisms that result from an age-related loss of peripheral sensitivity. In light of our observations, these age-related changes in sensory function should be considered when investigating cellular, cortical, and behavioral functions throughout the lifespan in these commonly used C57BL/6J and CBA/CaJ mouse models. Copyright © 2012 Wiley Periodicals, Inc.

Identification of age-dependent motor and neuropsychological behavioural abnormalities in a mouse model of Mucopolysaccharidosis Type II

PubMed Central

Gleitz, Hélène F. E.; O’Leary, Claire; Holley, Rebecca J.

2017-01-01

Severe mucopolysaccharidosis type II (MPS II) is a progressive lysosomal storage disease caused by mutations in the IDS gene, leading to a deficiency in the iduronate-2-sulfatase enzyme that is involved in heparan sulphate and dermatan sulphate catabolism. In constitutive form, MPS II is a multi-system disease characterised by progressive neurocognitive decline, severe skeletal abnormalities and hepatosplenomegaly. Although enzyme replacement therapy has been approved for treatment of peripheral organs, no therapy effectively treats the cognitive symptoms of the disease and novel therapies are in development to remediate this. Therapeutic efficacy and subsequent validation can be assessed using a variety of outcome measures that are translatable to clinical practice, such as behavioural measures. We sought to consolidate current knowledge of the cognitive, skeletal and motor abnormalities present in the MPS II mouse model by performing time course behavioural examinations of working memory, anxiety, activity levels, sociability and coordination and balance, up to 8 months of age. Cognitive decline associated with alterations in spatial working memory is detectable at 8 months of age in MPS II mice using spontaneous alternation, together with an altered response to novel environments and anxiolytic behaviour in the open-field. Coordination and balance on the accelerating rotarod were also significantly worse at 8 months, and may be associated with skeletal changes seen in MPS II mice. We demonstrate that the progressive nature of MPS II disease is also seen in the mouse model, and that cognitive and motor differences are detectable at 8 months of age using spontaneous alternation, the accelerating rotarod and the open-field tests. This study establishes neurological, motor and skeletal measures for use in pre-clinical studies to develop therapeutic approaches in MPS II. PMID:28207863

Coat color genetics of Peromyscus. I. Ashiness, an age-dependent coat color mutation in the deer mouse.

PubMed

Teed, S K; Crossland, J P; Dawson, W D

1990-01-01

Ashy deer mice (Peromyscus maniculatus) were first discovered about 1960 in a wild population from Oregon. Although indistinguishable from the wild type at weaning, ashy deer mice become progressively grayer with subsequent molts. The trait is inherited as an autosomal recessive and the symbol ahy is assigned for the locus. The trait is distinctly manifest by 6 months of age, at which time homozygotes have white hairs on the muzzle and at the base of the tail. The amount of white gradually increases with age, but development varies greatly among animals. Some become virtually all white by 18 months. Implants of melanocyte-stimulating hormone induced production of pigment in depigmented portions of the coat, indicating that viable melanocytes were present. The ashy deer mouse model may be useful for further study of melanocyte function.

White spotting variant (Wv) mouse as an experimental model for ovarian aging and menopausal biology

PubMed Central

Smith, Elizabeth R.; Yeasky, Toni; Wei, Jain Qin; Miki, Roberto A.; Cai, Kathy Q.; Smedberg, Jennifer L.; Yang, Wan-Lin; Xu, Xiang-Xi

2011-01-01

Objective Menopause is a unique phenomenon in modern women, as most mammalian species possess a reproductive period comparable to their lifespan. Menopause is caused by the depletion of germ cell-containing ovarian follicles, and in laboratory studies is usually modeled in animals in which the ovarian function is removed by ovariectomy or chemical poisoning of the germ cells. Our objective was to explore and characterize the white spotting variant (Wv) mice that have reduced ovarian germ cell abundance, a result of a point mutation in the c-kit gene that decreases the kinase activity, as a genetic model for use in menopausal studies. Methods Physiological and morphological features associated with menopause were determined in female Wv/Wv mice compared to age-matched wildtype controls. Immunohistochemistry was used to evaluate the presence and number of follicles in paraffin-embedded ovaries. Bone density and body composition were evaluated using the PIXImus X-ray densitometer, and lipids, calcium, and hormone levels were determined in serum using antigen-specific EIAs. Heart and body weight were measured, and cardiac function was evaluated by transthoracic echocardiography. Results The ovaries of the Wv/Wv females have a greatly reduced number of normal germ cells at birth compared to wildtype mice. The remaining follicles are depleted by around 2 months, and the ovaries develop benign epithelial lesions that resemble morphological changes that occur during ovarian aging, whereas a normal mouse ovary has numerous follicles at all stages of development and retains some follicles even in advanced age. Wv mice have elevated plasma gonadotrophins and reduced estrogen and progesterone levels, a significant reduction in bone mass density, and elevated serum cholesterol and lipoprotein levels. Moreover, the Wv female mice have enlarged hearts and reduced cardiac function. Conclusions The reduction of c-kit activity in Wv mice leads to a substantially diminished

True lemurs…true species - species delimitation using multiple data sources in the brown lemur complex

PubMed Central

2013-01-01

Background Species are the fundamental units in evolutionary biology. However, defining them as evolutionary independent lineages requires integration of several independent sources of information in order to develop robust hypotheses for taxonomic classification. Here, we exemplarily propose an integrative framework for species delimitation in the “brown lemur complex” (BLC) of Madagascar, which consists of seven allopatric populations of the genus Eulemur (Primates: Lemuridae), which were sampled extensively across northern, eastern and western Madagascar to collect fecal samples for DNA extraction as well as recordings of vocalizations. Our data base was extended by including museum specimens with reliable identification and locality information for skull shape and pelage color analysis. Results Between-group analyses of principal components revealed significant heterogeneity in skull shape, pelage color variation and loud calls across all seven populations. Furthermore, post-hoc statistical tests between pairs of populations revealed considerable discordance among different data sets for different dyads. Despite a high degree of incomplete lineage sorting among nuclear loci, significant exclusive ancestry was found for all populations, except for E. cinereiceps, based on one mitochondrial and three nuclear genetic loci. Conclusions Using several independent lines of evidence, our results confirm the species status of the members of the BLC under the general lineage concept of species. More generally, the present analyses demonstrate the importance and value of integrating different kinds of data in delimiting recently evolved radiations. PMID:24159931

Loss of Pgc-1α expression in aging mouse muscle potentiates glucose intolerance and systemic inflammation.

PubMed

Sczelecki, Sarah; Besse-Patin, Aurèle; Abboud, Alexandra; Kleiner, Sandra; Laznik-Bogoslavski, Dina; Wrann, Christiane D; Ruas, Jorge L; Haibe-Kains, Benjamin; Estall, Jennifer L

2014-01-15

Diabetes risk increases significantly with age and correlates with lower oxidative capacity in muscle. Decreased expression of peroxisome proliferator-activated receptor-γ coactivator-1α (Pgc-1α) and target gene pathways involved in mitochondrial oxidative phosphorylation are associated with muscle insulin resistance, but a causative role has not been established. We sought to determine whether a decline in Pgc-1α and oxidative gene expression occurs during aging and potentiates the development of age-associated insulin resistance. Muscle-specific Pgc-1α knockout (MKO) mice and wild-type littermate controls were aged for 2 yr. Genetic signatures of skeletal muscle (microarray and mRNA expression) and metabolic profiles (glucose homeostasis, mitochondrial metabolism, body composition, lipids, and indirect calorimetry) of mice were compared at 3, 12, and 24 mo of age. Microarray and gene set enrichment analysis highlighted decreased function of the electron transport chain as characteristic of both aging muscle and loss of Pgc-1α expression. Despite significant reductions in oxidative gene expression and succinate dehydrogenase activity, young mice lacking Pgc-1α in muscle had lower fasting glucose and insulin. Consistent with loss of oxidative capacity during aging, Pgc-1α and Pgc-1β expression were reduced in aged wild-type mouse muscle. Interestingly, the combination of age and loss of muscle Pgc-1α expression impaired glucose tolerance and led to increased fat mass, insulin resistance, and inflammatory markers in white adipose and liver tissues. Therefore, loss of Pgc-1α expression and decreased mitochondrial oxidative capacity contribute to worsening glucose tolerance and chronic systemic inflammation associated with aging.

SIRT1 signalling protects mouse oocytes against oxidative stress and is deregulated during aging.

PubMed

Di Emidio, Giovanna; Falone, Stefano; Vitti, Maurizio; D'Alessandro, Anna Maria; Vento, Marilena; Di Pietro, Cinzia; Amicarelli, Fernanda; Tatone, Carla

2014-09-01

Is SIRT1 involved in the oxidative stress (OS) response in mouse oocytes? SIRT1 plays a pivotal role in the adaptive response of mouse germinal vesicle (GV) oocytes to OS and promotes a signalling cascade leading to up-regulation of the MnSod gene. OS is known to continuously threaten acquisition and maintenance of oocyte developmental potential during in vivo processes and in vitro manipulations. Previous studies in somatic cells have provided strong evidence for the role of SIRT1 as a sensor of the cell redox state and a protector against OS and aging. GV oocytes obtained from young (4-8 weeks) and reproductively old (48-52 weeks) CD1 mice were blocked in the prophase stage by 0.5 µM cilostamide. Groups of 30 oocytes were exposed to 25 µM H2O2 and processed following different times for the analysis of intracellular localization of SIRT1 and FOXO3A, and evaluation of Sirt1, miRNA-132, FoxO3a and MnSod gene expression. Another set of oocytes was cultured in the presence or absence of the SIRT1-specific inhibitor Ex527, and exposed to H2O2 in order to assess the involvement of SIRT1 in the activation of a FoxO3a-MnSod axis and ROS detoxification. In the last part of this study, GV oocytes were maturated in vitro in the presence of different Ex527 concentrations (0, 2.5, 5, 10, 20 µM) and assessed for maturation rates following 16 h. Effects of Ex527 on spindle morphology and ROS levels were also evaluated. SIRT1 and FOXO3A intracellular distribution in response to OS was investigated by immunocytochemistry. Real-time RT-PCR was employed to analyse Sirt1, miR-132, FoxO3a and MnSod gene expression. Reactive oxygen species (ROS) production was evaluated by in vivo measurement of carboxy-H2DCF diacetate labelling. Spindle and chromosomal distribution in in vitro matured oocytes were analysed by immunocytochemistry and DNA fluorescent labelling, respectively. Specific changes in the intracellular localization of SIRT1 and up-regulation of Sirt1 gene were detected in

Transmission of trisomy decreases with maternal age in mouse models of Down syndrome, mirroring a phenomenon in human Down syndrome mothers.

PubMed

Stern, Shani; Biron, David; Moses, Elisha

2016-07-11

Down syndrome incidence in humans increases dramatically with maternal age. This is mainly the result of increased meiotic errors, but factors such as differences in abortion rate may play a role as well. Since the meiotic error rate increases almost exponentially after a certain age, its contribution to the overall incidence aneuploidy may mask the contribution of other processes. To focus on such selection mechanisms we investigated transmission in trisomic females, using data from mouse models and from Down syndrome humans. In trisomic females the a-priori probability for trisomy is independent of meiotic errors and thus approximately constant in the early embryo. Despite this, the rate of transmission of the extra chromosome decreases with age in females of the Ts65Dn and, as we show, for the Tc1 mouse models for Down syndrome. Evaluating progeny of 73 Tc1 births and 112 Ts65Dn births from females aged 130 days to 250 days old showed that both models exhibit a 3-fold reduction of the probability to transmit the trisomy with increased maternal ageing. This is concurrent with a 2-fold reduction of litter size with maternal ageing. Furthermore, analysis of previously reported 30 births in Down syndrome women shows a similar tendency with an almost three fold reduction in the probability to have a Down syndrome child between a 20 and 30 years old Down syndrome woman. In the two types of mice models for Down syndrome that were used for this study, and in human Down syndrome, older females have significantly lower probability to transmit the trisomy to the offspring. Our findings, taken together with previous reports of decreased supportive environment of the older uterus, add support to the notion that an older uterus negatively selects the less fit trisomic embryos.

Age-dependent increment of hydroxymethylation in the brain cortex in the triple-transgenic mouse model of Alzheimer's disease.

PubMed

Cadena-del-Castillo, Carla; Valdes-Quezada, Christian; Carmona-Aldana, Francisco; Arias, Clorinda; Bermúdez-Rattoni, Federico; Recillas-Targa, Félix

2014-01-01

Alzheimer's disease (AD) is a complex disorder whose etiology is associated with environmental and genetic factors. Recently there have been several attempts to analyze the role of epigenetic alterations in the origin and progression of this neurodegenerative condition. To evaluate the potential participation of the methylation status of the genome that may contribute to AD progression, we have studied the levels and distribution of the 5-methylcytosine and 5-hydroxymethylcytosine in different brain regions at different ages. We analyzed and quantified the immunosignal of these two epigenetic marks in young versus old wild-type mice and in the triple-transgenic mouse model of AD (3xTg-AD). The results show a decline in global 5-methylcytosine mark over time in all studied brain regions concomitant with a significant and widespread increase in 5-hydroxymethylcytosine mark in the aged transgenic mice in contrast to the age-matched controls. These differences in the methylation pattern of brain DNA in the 3xTg-AD that accumulates along age indicates abnormal formation of permissive chromatin structure associated with the increase in AD-related markers.

Apigenin exhibits protective effects in a mouse model of d-galactose-induced aging via activating the Nrf2 pathway.

PubMed

Sang, Ying; Zhang, Fan; Wang, Heng; Yao, Jianqiao; Chen, Ruichuan; Zhou, Zhengdao; Yang, Kun; Xie, Yan; Wan, Tianfeng; Ding, Hong

2017-06-21

The aim of the present research was to study the protective effects and underlying mechanisms of apigenin on d-galactose-induced aging mice. Firstly, apigenin exhibited a potent antioxidant activity in vitro. Secondly, d-galactose was administered by subcutaneous injection once daily for 8 weeks to establish an aging mouse model to investigate the protective effect of apigenin. We found that apigenin supplementation significantly ameliorated aging-related changes such as behavioral impairment, decreased organic index, histopathological injury, increased senescence-associated β-galactosidase (SAβ-gal) activity and advanced glycation end product (AGE) level. Further data showed that apigenin facilitated Nrf2 nuclear translocation both in aging mice and normal young mice, and the Nrf2 expression of normal young mice was higher than that of natural senile mice. In addition, the expressions of Nrf2 downstream gene targets, including HO-1 and NQO1, were also promoted by apigenin administration. Moreover, apigenin also decreased the MDA level and elevated SOD and CAT activities. In conclusion, focusing on the Nrf2 pathway is a suitable strategy to delay the aging process, and apigenin may exert an anti-senescent effect process via activating the Nrf2 pathway.

Postnatal development, maturation and aging in the mouse cochlea and their effects on hair cell regeneration

PubMed Central

Walters, Brad; Zuo, Jian

2012-01-01

The organ of Corti in the mammalian inner ear is comprised of mechanosensory hair cells (HCs) and nonsensory supporting cells (SCs), both of which are believed to be terminally postmitotic beyond late embryonic ages. Consequently, regeneration of HCs and SCs does not occur naturally in the adult mammalian cochlea, though recent evidence suggests that these cells may not be completely or irreversibly quiescent in at earlier postnatal ages. Furthermore, regenerative processes can be induced by genetic and pharmacological manipulations, but, more and more reports suggest that regenerative potential declines as the organ of Corti continues to age. In numerous mammalian systems, such effects of aging on regenerative potential are well established. However, in the cochlea, the problem of regeneration has not been traditionally viewed as one of aging. This is an important consideration as current models are unable to elicit widespread regeneration or full recovery of function at adult ages yet regenerative therapies will need to be developed specifically for adult populations. Still, the advent of gene targeting and other genetic manipulations has established mice as critically important models for the study of cochlear development and HC regeneration and suggests that auditory HC regeneration in adult mammals may indeed be possible. Thus, this review will focus on the pursuit of regeneration in the postnatal and adult mouse cochlea and highlight processes that occur during postnatal development, maturation, and aging that could contribute to an age-related decline in regenerative potential. Second, we will draw upon the wealth of knowledge pertaining to age related senescence in tissues outside of the ear to synthesize new insights and potentially guide future research aimed at promoting HC regeneration in the adult cochlea. PMID:23164734

Age-related cochlear cytokine gene expression in the BALB/cJ mouse with systemic versus intratympanic dosing of steroid drugs.

PubMed

Tokarz, Sara A; Pang, Jiaqing; Grosz, Anna; Kempton, J Beth; Trune, Dennis R; Pillers, De-Ann M

2013-07-01

Age-related differences in the expression of inflammatory cytokines in the inner ear may contribute to the development of age-related hearing loss (ARHL). ARHL is characterized by tissue remodeling, ischemia, ion homeostasis, and inflammation. Steroid therapy is an otoprotective strategy that likely acts by reducing inflammation. We examined age-related changes in cytokine gene expression in the cochlea of the BALB/cJ mouse model of premature ARHL after systemic or intratympanic steroid delivery. 'Young' (2.5-3 months) and 'Old' (5-9 months) mice were treated with dexamethasone or fludrocortisone administered either orally or intratympanically. Cytokine gene expression in cochlear RNA was analyzed using prefabricated cDNA arrays. Old groups were compared to Young groups to identify age-related changes. Down-regulation of a cytokine associated with bone remodeling (SPP1) was observed in the untreated Old group. Numerous genes were up- or down-regulated by more than twofold by steroid treatment, including proinflammatory interleukins (IL-16) and anti-inflammatory cytokines.

The effects of aging, housing and ibuprofen treatment on brain neurochemistry in a triple transgene Alzheimer's disease mouse model using magnetic resonance spectroscopy and imaging.

PubMed

Choi, Ji-Kyung; Carreras, Isabel; Aytan, Nur; Jenkins-Sahlin, Eric; Dedeoglu, Alpaslan; Jenkins, Bruce G

2014-11-24

We investigated a triple transgene Alzheimer's disease (AD) mouse model that recapitulates many of the neurochemical, anatomic, pathologic and behavioral defects seen in human AD. We studied the mice as a function of age and brain region and investigated potential therapy with the non-steroidal anti-inflammatory drug ibuprofen. Magnetic resonance spectroscopy (MRS) showed alterations characteristic of AD (i.e. increased myo-inositol and decreased N-acetylaspartate (NAA)). Mice at 6 months of age showed an increase in myo-inositol in the hippocampus at a time when the Aβ is intracellular, but not in amygdala or cortex. Myo-inositol increased as a function of age in the amygdala, cortex and striatum while NAA decreased only in the hippocampus and cortex at 17-23 months of age. Ibuprofen protected the increase of myo-inositol at six months of age in the hippocampus, but had no effect at 17-23 months of age (a time when Aβ is extracellular). In vivo MRI and MRS showed that at 17-23 months of age there was a significant protective effect of ibuprofen on hippocampal volume and NAA loss. Together, these data show the following: the increase in myo-inositol occurs before the decrease in NAA in hippocampus but not cortex; the hippocampus shows earlier changes than does the amygdale or cortex consistent with earlier deposition of Aβ40-42 in the hippocampus and ibuprofen protects against multiple components of the AD pathology. These data also show a profound effect of housing on this particular mouse model. Published by Elsevier B.V.

Joint loads resulting in ACL rupture: Effects of age, sex, and body mass on injury load and mode of failure in a mouse model.

PubMed

Blaker, Carina L; Little, Christopher B; Clarke, Elizabeth C

2017-08-01

Anterior cruciate ligament (ACL) tears are a common knee injury with a known but poorly understood association with secondary joint injuries and post-traumatic osteoarthritis (OA). Female sex and age are known risk factors for ACL injury but these variables are rarely explored in mouse models of injury. This study aimed to further characterize a non-surgical ACL injury model to determine its clinical relevance across a wider range of mouse specifications. Cadaveric and anesthetized C57BL/6 mice (9-52 weeks of age) underwent joint loading to investigate the effects of age, sex, and body mass on ACL injury mechanisms. The ACL injury load (whole joint load required to rupture the ACL) was measured from force-displacement data, and mode of failure was assessed using micro-dissection and histology. ACL injury load was found to increase with body mass and age (p < 0.001) but age was not significant when controlling for mass. Sex had no effect. In contrast, the mode of ACL failure varied with both age and sex groups. Avulsion fractures (complete or mixed with mid-substance tears) were common in all age groups but the proportion of mixed and mid-substance failures increased with age. Females were more likely than males to have a major avulsion relative to a mid-substance tear (p < 0.01). This data compliments studies in human cadaveric knees, and provides a basis for determining the severity of joint injury relative to a major ACL tear in mice, and for selecting joint loading conditions in future experiments using this model. © 2016 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 35:1754-1763, 2017. © 2016 Orthopaedic Research Society. Published by Wiley Periodicals, Inc.

Histological and reference system for the analysis of mouse intervertebral disc.

PubMed

Tam, Vivian; Chan, Wilson C W; Leung, Victor Y L; Cheah, Kathryn S E; Cheung, Kenneth M C; Sakai, Daisuke; McCann, Matthew R; Bedore, Jake; Séguin, Cheryle A; Chan, Danny

2018-01-01

A new scoring system based on histo-morphology of mouse intervertebral disc (IVD) was established to assess changes in different mouse models of IVD degeneration and repair. IVDs from mouse strains of different ages, transgenic mice, or models of artificially induced IVD degeneration were assessed. Morphological features consistently observed in normal, and early/later stages of degeneration were categorized into a scoring system focused on nucleus pulposus (NP) and annulus fibrosus (AF) changes. "Normal NP" exhibited a highly cellularized cell mass that decreased with natural ageing and in disc degeneration. "Normal AF" consisted of distinct concentric lamellar structures, which was disrupted in severe degeneration. NP/AF clefts indicated more severe changes. Consistent scores were obtained between experienced and new users. Altogether, our scoring system effectively differentiated IVD changes in various strains of wild-type and genetically modified mice and in induced models of IVD degeneration, and is applicable from the post-natal stage to the aged mouse. This scoring tool and reference resource addresses a pressing need in the field for studying IVD changes and cross-study comparisons in mice, and facilitates a means to normalize mouse IVD assessment between different laboratories. © 2017 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 36:233-243, 2018. © 2017 Orthopaedic Research Society. Published by Wiley Periodicals, Inc.

Protective effects of ethanol extracts of Artemisia asiatica Nakai ex Pamp. on ageing-induced deterioration in mouse oocyte quality.

PubMed

Jeon, Hyuk-Joon; You, Seung Yeop; Kim, Dong Hyun; Jeon, Hong Bae; Oh, Jeong Su

2017-08-01

Following ovulation, oocytes undergo a time-dependent deterioration in quality referred to as post-ovulatory ageing. Although various factors influence the post-ovulatory ageing of oocytes, oxidative stress is a key factor involved in deterioration of oocyte quality. Artemisia asiatica Nakai ex Pamp. has been widely used in East Asia as a food ingredient and traditional medicine for the treatment of inflammation, cancer, and microbial infections. Recent studies have shown that A. asiatica exhibits antioxidative effects. In this study, we investigated whether A. asiatica has the potential to attenuate deterioration in oocyte quality during post-ovulatory ageing. Freshly ovulated mouse oocytes were cultured with 0, 50, 100 or 200 μg/ml ethanol extracts of A. asiatica Nakai ex Pamp. After culture for up to 24 h, various ageing-induced oocyte abnormalities, including morphological changes, reactive oxygen species (ROS) accumulation, apoptosis, chromosome and spindle defects, and mitochondrial aggregation were determined. Treatment of oocytes with A. asiatica extracts reduced ageing-induced morphological changes. Moreover, A. asiatica extracts decreased ROS generation and the onset of apoptosis by preventing elevation of the Bax/Bcl-2 expression ratio during post-ovulatory ageing. Furthermore, A. asiatica extracts attenuated the ageing-induced abnormalities including spindle defects, chromosome misalignment and mitochondrial aggregation. Our results demonstrate that A. asiatica can relieve deterioration in oocyte quality and delay the onset of apoptosis during post-ovulatory ageing.

Lipopolysaccharide administration in the dominant mouse destabilizes social hierarchy.

PubMed

Cohn, Daniel Wagner Hamada; Gabanyi, Ilana; Kinoshita, Denise; de Sá-Rocha, Luiz Carlos

2012-09-01

Sickness behavior is a set of behavioral changes that are part of an adaptive strategy to overcome infection. Mice that interact with conspecifics displaying sickness behavior also show relevant behavioral changes. In this work we sought to determine the role of sickness behavior display by a dominant mouse as a promoter of hierarchy instability. We treated the dominant mouse within a dyad with lipopolysaccharide (LPS) (400 μg/kg, i.p.) for three consecutive days and assessed social dominance behavior. Since elder animals display increased inflammatory responses and the behaviors toward conspecifics are influenced by kinship we also assessed whether kinship and age, might influence sickness related hierarchy instability. Our results show that administration of LPS in the dominant mouse promotes social instability within a dyad, and indicates that this instability could be influenced by kinship and age. Copyright © 2012 Elsevier B.V. All rights reserved.

Conditional ablation of the choroideremia gene causes age-related changes in mouse retinal pigment epithelium.

PubMed

Wavre-Shapton, Silène T; Tolmachova, Tanya; Lopes da Silva, Mafalda; da Silva, Mafalda Lopes; Futter, Clare E; Seabra, Miguel C

2013-01-01

The retinal pigment epithelium (RPE) is a pigmented monolayer of cells lying between the photoreceptors and a layer of fenestrated capillaries, the choriocapillaris. Choroideremia (CHM) is an X-linked progressive degeneration of these three layers caused by the loss of function of Rab Escort protein-1 (REP1). REP1 is involved in the prenylation of Rab proteins, key regulators of membrane trafficking. To study the pathological consequences of chronic disruption of membrane traffic in the RPE we used a cell type-specific knock-out mouse model of the disease, where the Chm/Rep1 gene is deleted only in pigmented cells (Chm(Flox), Tyr-Cre+). Transmission electron microscopy (TEM) was used to quantitate the melanosome distribution in the RPE and immunofluorescent staining of rhodopsin was used to quantitate phagocytosed rod outer segments in retinal sections. The ultrastructure of the RPE and Bruch's membrane at different ages was characterised by TEM to analyse age-related changes occurring as a result of defects in membrane traffic pathways. Chm/Rep1 gene knockout in RPE cells resulted in reduced numbers of melanosomes in the apical processes and delayed phagosome degradation. In addition, the RPE accumulated pathological changes at 5-6 months of age similar to those observed in 2-year old controls. These included the intracellular accumulation of lipofuscin-containing deposits, disorganised basal infoldings and the extracellular accumulation of basal laminar and basal linear deposits. The phenotype of the Chm(Flox), Tyr-Cre+ mice suggests that loss of the Chm/Rep1 gene causes premature accumulation of features of aging in the RPE. Furthermore, the striking similarities between the present observations and some of the phenotypes reported in age-related macular degeneration (AMD) suggest that membrane traffic defects may contribute to the pathogenesis of AMD.

Light pollution modifies the expression of daily rhythms and behavior patterns in a nocturnal primate.

PubMed

Le Tallec, Thomas; Perret, Martine; Théry, Marc

2013-01-01

Among anthropogenic pressures, light pollution altering light/dark cycles and changing the nocturnal component of the environment constitutes a threat for biodiversity. Light pollution is widely spread across the world and continuously growing. However, despite the efforts realized to describe and understand the effects of artificial lighting on fauna, few studies have documented its consequences on biological rhythms, behavioral and physiological functions in nocturnal mammals. To determine the impacts of light pollution on nocturnal mammals an experimental study was conducted on a nocturnal primate, the grey mouse lemur Microcebus murinus. Male mouse lemurs (N = 8) were exposed 14 nights to moonlight treatment and then exposed 14 nights to light pollution treatment. For both treatments, chronobiological parameters related to locomotor activity and core temperature were recorded using telemetric transmitters. In addition, at the end of each treatment, the 14(th) night, nocturnal and feeding behaviors were explored using an infrared camera. Finally, throughout the study, body mass and daily caloric food intake were recorded. For the first time in a nocturnal primate, light pollution was demonstrated to modify daily rhythms of locomotor activity and core temperature especially through phase delays and increases in core temperature. Moreover, nocturnal activity and feeding behaviors patterns were modified negatively. This study suggests that light pollution induces daily desynchronization of biological rhythms and could lead to seasonal desynchronization with potential deleterious consequences for animals in terms of adaptation and anticipation of environmental changes.

Light Pollution Modifies the Expression of Daily Rhythms and Behavior Patterns in a Nocturnal Primate

PubMed Central

Le Tallec, Thomas; Perret, Martine; Théry, Marc

2013-01-01

Among anthropogenic pressures, light pollution altering light/dark cycles and changing the nocturnal component of the environment constitutes a threat for biodiversity. Light pollution is widely spread across the world and continuously growing. However, despite the efforts realized to describe and understand the effects of artificial lighting on fauna, few studies have documented its consequences on biological rhythms, behavioral and physiological functions in nocturnal mammals. To determine the impacts of light pollution on nocturnal mammals an experimental study was conducted on a nocturnal primate, the grey mouse lemur Microcebus murinus. Male mouse lemurs (N = 8) were exposed 14 nights to moonlight treatment and then exposed 14 nights to light pollution treatment. For both treatments, chronobiological parameters related to locomotor activity and core temperature were recorded using telemetric transmitters. In addition, at the end of each treatment, the 14th night, nocturnal and feeding behaviors were explored using an infrared camera. Finally, throughout the study, body mass and daily caloric food intake were recorded. For the first time in a nocturnal primate, light pollution was demonstrated to modify daily rhythms of locomotor activity and core temperature especially through phase delays and increases in core temperature. Moreover, nocturnal activity and feeding behaviors patterns were modified negatively. This study suggests that light pollution induces daily desynchronization of biological rhythms and could lead to seasonal desynchronization with potential deleterious consequences for animals in terms of adaptation and anticipation of environmental changes. PMID:24236115

The menopausal mouse: a new neural paradigm of a distressing human condition.

PubMed

Danilovich, Natalia; Sairam, M Ram; Maysinger, Dusica

2003-08-26

Progressive and long-term sex hormone imbalance in the FSH-R haploinsufficient menopausal mouse leads to degenerative changes in the CNS associated with increased anxiety. The brain region most affected by aging in these mice is the hippocampus. Choline acetyltransferase (ChAT) enzymatic activity and synapsin immunoreactivity are reduced at 20 months of age. Neurons in the dentate gyrus show signs of progressive degenerative changes, hypertrophy and glyosis, and subsequent cell shrinkage and death. These results suggest that the menopausal mouse mimics degenerative changes in the hippocampus of hormonally imbalanced aging humans. We propose using this animal model to test the effectiveness of potential therapeutics in paradigms of accelerated aging.

Effects of Computer Skill on Mouse Move and Click Performance

ERIC Educational Resources Information Center

Panagiotakopoulos, Chris; Sarris, Menelaos

2008-01-01

This study focuses on the use of computers in the field of education. It reports a series of experimental mouse move and click tasks on constant and moving stimuli. These experiments attempt to explore the efficiency with which individuals of different skill level and age group perform using a mouse. Differences in performance between high-skill…

Deep sequencing identifies circulating mouse miRNAs that are functionally implicated in manifestations of aging and responsive to calorie restriction.

PubMed

Dhahbi, Joseph M; Spindler, Stephen R; Atamna, Hani; Yamakawa, Amy; Guerrero, Noel; Boffelli, Dario; Mote, Patricia; Martin, David I K

2013-02-01

MicroRNAs (miRNAs) function to modulate gene expression, and through this property they regulate a broad spectrum of cellular processes. They can circulate in blood and thereby mediate cell-to-cell communication. Aging involves changes in many cellular processes that are potentially regulated by miRNAs, and some evidence has implicated circulating miRNAs in the aging process. In order to initiate a comprehensive assessment of the role of circulating miRNAs in aging, we have used deep sequencing to characterize circulating miRNAs in the serum of young mice, old mice, and old mice maintained on calorie restriction (CR). Deep sequencing identifies a set of novel miRNAs, and also accurately measures all known miRNAs present in serum. This analysis demonstrates that the levels of many miRNAs circulating in the mouse are increased with age, and that the increases can be antagonized by CR. The genes targeted by this set of age-modulated miRNAs are predicted to regulate biological processes directly relevant to the manifestations of aging including metabolic changes, and the miRNAs themselves have been linked to diseases associated with old age. This finding implicates circulating miRNAs in the aging process, raising questions about their tissues of origin, their cellular targets, and their functional role in metabolic changes that occur with aging.

Carrageenan-induced mouse paw oedema is biphasic, age-weight dependent and displays differential nitric oxide cyclooxygenase-2 expression

PubMed Central

Posadas, Inmaculada; Bucci, Mariarosaria; Roviezzo, Fiorentina; Rossi, Antonietta; Parente, Luca; Sautebin, Lidia; Cirino, Giuseppe

2004-01-01

Injection of carrageenan 1% (50 μl) in the mouse paw causes a biphasic response: an early inflammatory response that lasts 6 h and a second late response that peaks at 72 h, declining at 96 h. Only mice 7- or 8-week old, weighing 32–34 g, displayed a consistent response in both phases. In 8-week-old mice, myeloperoxidase (MPO) levels are significantly elevated in the early phase at 6 h and reach their maximum at 24 h to decline to basal value at 48 h. Nitrate+nitrite (NOx) levels in the paw are maximal after 2 h and slowly decline thereafter in contrast to prostaglandin E2 levels that peak in the second phase at the 72 h point. Western blot analysis showed that inducible nitric oxide synthase (iNOS) is detectable at 6 h and cyclooxygenase 2 (COX-2) at 24 h point, respectively. Analysis of endothelial nitric oxide synthase (eNOS), iNOS and COX-2 expression at 6 and 24 h in 3–8-week-old mice demonstrated that both eNOS and iNOS expressions are dependent upon the age–weight of mice, as opposite to COX-2 that is present only in the second phase of the oedema and is not linked to mouse age–weight. Subplantar injection of carrageenan to C57BL/6J causes a biphasic oedema that is significantly reduced by about 20% when compared to CD1 mice. Interestingly, in these mice, iNOS expression is absent up to 6 h, as opposite to CD1, and becomes detectable at the 24 h point. Cyclooxygenase (COX-1) expression is upregulated between 4 and 24 h after carrageenan injection, whereas in CD1 mice COX-1 remains unchanged after irritant agent injection. MPO levels are maximal at the 24 h point and they are significantly lower, at 6 h point, than MPO levels detected in CD1 mice. In conclusion, mouse paw oedema is biphasic and age-weight dependent. The present results are the first report on the differential expressions of eNOS, iNOS, COX-1 and COX-2 in response to carrageenan injection in the two phases of the mouse paw oedema. PMID:15155540

AGE-RELATED FUNCTIONAL AND HISTOPATHOLOGICAL CHANGES OF THE EAR IN THE MPS I MOUSE

PubMed Central

Schachern, Patricia A.; Cureoglu, Sebahattin; Tsuprun, Vladimir; Paparella, Michael M.; Whitley, Chester

2007-01-01

Objective Mucopolysaccharidosis type I (MPS I) is an autosomal recessive disorder caused by a mutation in the gene encoding the enzyme α-L-iduronidase. This enzyme is responsible for degradation of dermatan and heparan sulfates. Enzyme deficiency results in their accumulation in lysosomes of virtually all organs, resulting in severe somatic and neurological changes. Clinical findings of otitis media with mixed hearing loss are common. Cellular and molecular mechanisms of ear pathology and hearing loss are not understood. The purpose of this study is to describe the age-related audiologic and histopathologic changes of the ear in the mouse model of MPS I. Methods Auditory brainstemresponses (ABR) were obtained to clicks and tone bursts at 1-32 kHz, and pathological changes to middle and inner ears were studied with light and electron microscopy in fifty-three mice that included: 1) wild type (+/+) - five at 2 months, five at 4 to 6 months, and five at 13 to 19 months; 2) heterozygotes (+/−) - four at 2 months; five at 4 to 6 months; and eight at 13 to 19 months; and 3) homozygotes (−/−); five at 2 months; six at 4 to 6 months; and five at 13 to 19 months. Histopathology was also done on five newborn −/− mice. Results In newborns no lysosomal storage was observed and the ear appeared age appropriately normal. In all other −/− mice, cells with lysosomal storage vacuoles were observed in spiral ligament, spiral prominence, spiral limbus, basilar membrane, epithelial and mesothelial cells of Reissner’s membrane, endothelial cells of vessels, and some ganglion cells; their number increased with aging. Hair cell loss was not observed at 2 or 6 months, but there was total loss of the organ of Corti in year-old mice. Hearing of −/− mice was significantly decreased at all ages compared to +/+ and +/−. Hearing loss progressed from mild to moderate loss at 2 months to profound at 6 months and total deafness by one year of age. Conclusions Progressive age

Attentional function and basal forebrain cholinergic neuron morphology during aging in the Ts65Dn mouse model of Down syndrome

PubMed Central

Powers, Brian E.; Velazquez, Ramon; Kelley, Christy M.; Ash, Jessica A.; Strawderman, Myla S.; Alldred, Melissa J.; Ginsberg, Stephen D.; Mufson, Elliott J.

2016-01-01

Individuals with Down syndrome (DS) exhibit intellectual disability and develop Alzheimer's disease-like neuropathology during the third decade of life. The Ts65Dn mouse model of DS exhibits key features of both disorders, including impairments in learning, attention and memory, as well as atrophy of basal forebrain cholinergic neurons (BFCNs). The present study evaluated attentional function in relation to BFCN morphology in young (3 months) and middle-aged (12 months) Ts65Dn mice and disomic (2N) controls. Ts65Dn mice exhibited attentional dysfunction at both ages, with greater impairment in older trisomics. Density of BFCNs was significantly lower for Ts65Dn mice independent of age, which may contribute to attentional dysfunction since BFCN density was positively associated with performance on an attention task. BFCN volume decreased with age in 2N but not Ts65Dn mice. Paradoxically, BFCN volume was greater in older trisomic mice, suggestive of a compensatory response. In sum, attentional dysfunction occurred in both young and middle-aged Ts65Dn mice, which may in part reflect reduced density and/or phenotypic alterations in BFCNs. PMID:26719290

Attentional function and basal forebrain cholinergic neuron morphology during aging in the Ts65Dn mouse model of Down syndrome.

PubMed

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

2016-12-01

Individuals with Down syndrome (DS) exhibit intellectual disability and develop Alzheimer's disease-like neuropathology during the third decade of life. The Ts65Dn mouse model of DS exhibits key features of both disorders, including impairments in learning, attention and memory, as well as atrophy of basal forebrain cholinergic neurons (BFCNs). The present study evaluated attentional function in relation to BFCN morphology in young (3 months) and middle-aged (12 months) Ts65Dn mice and disomic (2N) controls. Ts65Dn mice exhibited attentional dysfunction at both ages, with greater impairment in older trisomics. Density of BFCNs was significantly lower for Ts65Dn mice independent of age, which may contribute to attentional dysfunction since BFCN density was positively associated with performance on an attention task. BFCN volume decreased with age in 2N but not Ts65Dn mice. Paradoxically, BFCN volume was greater in older trisomic mice, suggestive of a compensatory response. In sum, attentional dysfunction occurred in both young and middle-aged Ts65Dn mice, which may in part reflect reduced density and/or phenotypic alterations in BFCNs.

Mouse genome-wide association study identifies polymorphisms on chromosomes 4, 11, and 15 for age-related cardiac fibrosis.

PubMed

Li, Qiaoli; Berndt, Annerose; Sundberg, Beth A; Silva, Kathleen A; Kennedy, Victoria E; Cario, Clinton L; Richardson, Matthew A; Chase, Thomas H; Schofield, Paul N; Uitto, Jouni; Sundberg, John P

2016-06-01

Dystrophic cardiac calcinosis (DCC), also called epicardial and myocardial fibrosis and mineralization, has been detected in mice of a number of laboratory inbred strains, most commonly C3H/HeJ and DBA/2J. In previous mouse breeding studies between these DCC susceptible and the DCC-resistant strain C57BL/6J, 4 genetic loci harboring genes involved in DCC inheritance were identified and subsequently termed Dyscalc loci 1 through 4. Here, we report susceptibility to cardiac fibrosis, a sub-phenotype of DCC, at 12 and 20 months of age and close to natural death in a survey of 28 inbred mouse strains. Eight strains showed cardiac fibrosis with highest frequency and severity in the moribund mice. Using genotype and phenotype information of the 28 investigated strains, we performed genome-wide association studies (GWAS) and identified the most significant associations on chromosome (Chr) 15 at 72 million base pairs (Mb) (P < 10(-13)) and Chr 4 at 122 Mb (P < 10(-11)) and 134 Mb (P < 10(-7)). At the Chr 15 locus, Col22a1 and Kcnk9 were identified. Both have been reported to be morphologically and functionally important in the heart muscle. The strongest Chr 4 associations were located approximately 6 Mb away from the Dyscalc 2 quantitative trait locus peak within the boundaries of the Extl1 gene and in close proximity to the Trim63 and Cap1 genes. In addition, a single-nucleotide polymorphism association was found on chromosome 11. This study provides evidence for more than the previously reported 4 genetic loci determining cardiac fibrosis and DCC. The study also highlights the power of GWAS in the mouse for dissecting complex genetic traits.

Mouse genome-wide association study identifies polymorphisms on chromosomes 4, 11 and 15 for age-related cardiac fibrosis

PubMed Central

Li, Qiaoli; Berndt, Annerose; Sundberg, Beth A.; Silva, Kathleen A.; Kennedy, Victoria E.; Cario, Clinton L; Richardson, Matthew A.; Chase, Thomas H.; Schofield, Paul N.; Uitto, Jouni; Sundberg, John P.

2017-01-01

Dystrophic cardiac calcinosis (DCC), also called epicardial and myocardial fibrosis and mineralization, has been detected in mice of a number of laboratory inbred strains, most commonly C3H/HeJ and DBA/2J. In previous mouse breeding studies between these DCC susceptible and the DCC resistant strain C57BL/6J, 4 genetic loci harboring genes involved in DCC inheritance were identified and subsequently termed Dyscal loci 1 through 4. Here we report susceptibility to cardiac fibrosis, a sub-phenotype of DCC, at 12 and 20 months of age and close to natural death in a survey of 28 inbred mouse strains. Eight strains showed cardiac fibrosis with highest frequency and severity in the moribund mice. Using genotype and phenotype information of the 28 investigated strains we performed genome-wide association studies (GWAS) and identified the most significant associations on chromosome (Chr) 15 at 72 million base pairs (Mb) (P < 10−13) and Chr 4 at 122 Mb (P < 10−11) and 134 Mb (P < 10−7). At the Chr 15 locus Col22a1 and Kcnk9 were identified. Both have been reported to be morphologically and functionally important in the heart muscle. The strongest Chr 4 associations were located approximate 6 Mb away from the Dyscal 2 quantitative trait locus peak within the boundaries of the Extl1 gene and in close proximity to the Trim63 and Cap1 genes. In addition, a single nucleotide polymorphism association was found on chromosome 11. This study provides evidence for more than the previously reported 4 genetic loci determining cardiac fibrosis and DCC. The study also highlights the power of GWAS in the mouse for dissecting complex genetic traits. PMID:27126641

Mouse Phenome Database

PubMed Central

Grubb, Stephen C.; Bult, Carol J.; Bogue, Molly A.

2014-01-01

The Mouse Phenome Database (MPD; phenome.jax.org) was launched in 2001 as the data coordination center for the international Mouse Phenome Project. MPD integrates quantitative phenotype, gene expression and genotype data into a common annotated framework to facilitate query and analysis. MPD contains >3500 phenotype measurements or traits relevant to human health, including cancer, aging, cardiovascular disorders, obesity, infectious disease susceptibility, blood disorders, neurosensory disorders, drug addiction and toxicity. Since our 2012 NAR report, we have added >70 new data sets, including data from Collaborative Cross lines and Diversity Outbred mice. During this time we have completely revamped our homepage, improved search and navigational aspects of the MPD application, developed several web-enabled data analysis and visualization tools, annotated phenotype data to public ontologies, developed an ontology browser and released new single nucleotide polymorphism query functionality with much higher density coverage than before. Here, we summarize recent data acquisitions and describe our latest improvements. PMID:24243846

The anti-aging effects of LW-AFC via correcting immune dysfunctions in senescence accelerated mouse resistant 1 (SAMR1) strain.

PubMed

Wang, Jianhui; Cheng, Xiaorui; Zhang, Xiaorui; Cheng, Junping; Xu, Yiran; Zeng, Ju; Zhou, Wenxia; Zhang, Yongxiang

2016-05-10

Although there were considerable advances in the anti-aging medical field, it is short of therapeutic drug for anti-aging. Mounting evidence indicates that the immunosenescence is the key physiopathological mechanism of aging. This study showed the treatment of LW-AFC, an herbal medicine, decreased the grading score of senescence, increased weight, prolonged average life span and ameliorated spatial memory impairment in 12- and 24-month-old senescence accelerated mouse resistant 1 (SAMR1) strain. And these anti-aging effects of LW-AFC were more excellent than melatonin. The administration of LW-AFC enhanced ConA- and LPS-induced splenocyte proliferation in aged SAMR1 mice. The treatment of LW-AFC not only reversed the decreased the proportions of helper T cells, suppressor T cells and B cells, the increased regulatory T cells in the peripheral blood of old SAMR1 mice, but also could modulate the abnormal secretion of IL-1β, IL-2, IL-6, IL-17, IL-23, GM-CSF, IFN-γ, TNF-α, TNF-β, RANTES, eotaxin, MCP-1, IL-4, IL-5, IL-10 and G-CSF. These data indicated that LW-AFC reversed the immunosenescence status by restoring immunodeficiency and decreasing chronic inflammation and suggested LW-AFC may be an effective anti-aging agent.

Age-related decline in white matter integrity in a mouse model of tauopathy: an in vivo diffusion tensor magnetic resonance imaging study

PubMed Central

Sahara, Naruhiko; Perez, Pablo D.; Lin, Wen-Lang; Dickson, Dennis W.; Ren, Yan; Zeng, Huadong; Lewis, Jada; Febo, Marcelo

2016-01-01

Elevated expression of human hyperphosphorylated tau is associated with neuronal loss and white matter (WM) pathology in Alzheimer’s disease (AD) and related neurodegenerative disorders. Using in vivo diffusion tensor magnetic resonance imaging (DT-MRI) at 11.1 Tesla we measured age-related alterations in WM diffusion anisotropy indices in a mouse model of human tauopathy (rTg4510) and nontransgenic (nonTg) control mice at the age of 2.5, 4.5, and 8 months. Similar to previous DT-MRI studies in AD subjects, 8-month-old rTg4510 mice showed lower fractional anisotropy (FA) values in WM structures than nonTg. The low WM FA in rTg4510 mice was observed in the genu and splenium of the corpus callosum, anterior commissure, fimbria, and internal capsule and was associated with a higher radial diffusivity than nonTg. Interestingly, rTg4510 mice showed lower estimates for the mode of anisotropy than controls at 2.5 months suggesting that changes in this diffusivity metric are detectable at an early stage preceding severe tauopathy. Immunogold electron microscopy partly supports our diffusion tensor imaging findings. At the age of 4 months, rTg4510 mice show axonal tau inclusions and unmyelinated processes. At later ages (12 months and 14 months) we observed inclusions in myelin sheath, axons, and unmyelinated processes, and a “disorganized” pattern of myelinated fiber arrangement with enlarged inter-axonal spaces in rTg4510 but not in nonTg mice. Our data support a role for the progression of tau pathology in reduced WM integrity measured by DT-MRI. Further in vivo DT-MRI studies in the rTg4510 mouse should help better discern the detailed mechanisms of reduced FA and anisotropy mode, and the specific role of tau during neurodegeneration. PMID:24411290

Caffeine alleviates the deterioration of Ca2+ release mechanisms and fragmentation of in vitro aged mouse eggs

PubMed Central

Zhang, Nan; Wakai, Takuya; Fissore, Rafael. A.

2011-01-01

The developmental competence of mammalian eggs is compromised by postovulatory aging. We and others found that in these eggs the intracellular calcium ([Ca2+]i) responses required for egg activation and initiation of development are altered. Nevertheless, the mechanism(s) underlying this defective Ca2+ release is not well known. Here, we investigated if the function of IP3R1, the major Ca2+ release channel at fertilization, was undermined in in vitro aged mouse eggs. We found that in aged eggs IP3R1 displayed reduced function, as many of the changes acquired during maturation that enhance IP3R1 Ca2+ conductivity such as phosphorylation, receptor reorganization and increased Ca2+ store content ([Ca2+]ER) were lost with increasing postovulatory time. IP3R1 fragmentation, possibly associated with the activation of caspase-3, was also observed in these eggs. Many of these changes were prevented when the postovulatory aging of eggs was carried out in the presence of caffeine, which minimized the decline in IP3R1 function and maintained [Ca2+]ER content. Caffeine also maintained mitochondrial membrane potential as measured by JC-1 fluorescence. We therefore conclude that [Ca2+]i responses in aged eggs are undermined by reduced IP3R1 sensitivity, decreased [Ca2+]ER and compromised mitochondrial function, and that addition of caffeine ameliorates most of these aging-associated changes. Understanding the molecular basis of the protective effects of caffeine will be useful in elucidating, and possibly reversing, the signaling pathway(s) compromised by in vitro culture of eggs. PMID:22095868

Passive avoidance and complex maze learning in the senescence accelerated mouse (SAM): age and strain comparisons of SAM P8 and R1.

PubMed

Spangler, Edward L; Patel, Namisha; Speer, Dorey; Hyman, Michael; Hengemihle, John; Markowska, Alicja; Ingram, Donald K

2002-02-01

Two strains of the senescence accelerated mouse, P8 and R1,were tested in footshock-motivated passive avoidance (PA; P8, 3-21 months; R1, 3-24 months) and 14-unit T-maze (P8 and R1, 9, and 15 months) tasks. For PA, entry to a dark chamber from a lighted chamber was followed by a brief shock. Latency to enter the dark chamber 24 hours later served as a measure of retention. Two days of active avoidance training in a straight runway preceded 2 days (8 trials/day) of testing in the 14-unit T-maze. For PA retention, older P8 mice entered the dark chamber more quickly than older R1 mice, whereas no differences were observed between young P8 or R1 mice. In the 14-unit T-maze, age-related learning performance deficits were reflected in higher error scores for older mice. P8 mice were actually superior learners; that is, they had lower error scores compared with those of age-matched R1 counterparts. Although PA learning results were in agreement with other reports, results obtained in the 14-unit T-maze were not consistent with previous reports of learning impairments in the P8 senescence accelerated mouse.

Mouse models rarely mimic the transcriptome of human neurodegenerative diseases: A systematic bioinformatics-based critique of preclinical models.

PubMed

Burns, Terry C; Li, Matthew D; Mehta, Swapnil; Awad, Ahmed J; Morgan, Alexander A

2015-07-15

Translational research for neurodegenerative disease depends intimately upon animal models. Unfortunately, promising therapies developed using mouse models mostly fail in clinical trials, highlighting uncertainty about how well mouse models mimic human neurodegenerative disease at the molecular level. We compared the transcriptional signature of neurodegeneration in mouse models of Alzheimer׳s disease (AD), Parkinson׳s disease (PD), Huntington׳s disease (HD) and amyotrophic lateral sclerosis (ALS) to human disease. In contrast to aging, which demonstrated a conserved transcriptome between humans and mice, only 3 of 19 animal models showed significant enrichment for gene sets comprising the most dysregulated up- and down-regulated human genes. Spearman׳s correlation analysis revealed even healthy human aging to be more closely related to human neurodegeneration than any mouse model of AD, PD, ALS or HD. Remarkably, mouse models frequently upregulated stress response genes that were consistently downregulated in human diseases. Among potential alternate models of neurodegeneration, mouse prion disease outperformed all other disease-specific models. Even among the best available animal models, conserved differences between mouse and human transcriptomes were found across multiple animal model versus human disease comparisons, surprisingly, even including aging. Relative to mouse models, mouse disease signatures demonstrated consistent trends toward preserved mitochondrial function protein catabolism, DNA repair responses, and chromatin maintenance. These findings suggest a more complex and multifactorial pathophysiology in human neurodegeneration than is captured through standard animal models, and suggest that even among conserved physiological processes such as aging, mice are less prone to exhibit neurodegeneration-like changes. This work may help explain the poor track record of mouse-based translational therapies for neurodegeneration and provides a path

Pancreatic protective and hypoglycemic effects of Vitex agnus-castus L. fruit hydroalcoholic extract in D-galactose-induced aging mouse model

PubMed Central

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, D-galactose + VAC hydroalcoholic extract, aged, aged + VAC hydroalcoholic extract. The aged model was prepared by subcutaneous injection of D-galactose for 45 days and, VAC hydroalcoholic extract was gavaged twice a day in the last 7 days. 24 h after the last drug and extract administrations, serum samples and pancreatic tissues were removed to evaluate experimental and histological determinations. Serum glucose level decreased in VAC, D-galactose and, aged-treated groups compared to the control (P < 0.05). Insulin level increased in VAC and decreased in D-galactose and aged VAC-treated mice compared to the control (P < 0.05). Homeostasis model assessment-estimated insulin resistance (HOMA-IR) increased in D-galactose, aging, and VAC hydroalcoholic extract groups (P < 0.05) and, administration of VAC hydroalcoholic extract improved HOMA-IR in D-galactose and aging treated animals. Despite the size of pancreatic islets decreased in aged and D-galactose groups, VAC administration recovered it. Present data showed that VAC hydroalcoholic extract has hypoglycemic and pancreatic protective effects in natural aged and aging model mice. PMID:28515766

Pancreatic protective and hypoglycemic effects of Vitex agnus-castus L. fruit hydroalcoholic extract in D-galactose-induced aging mouse model.

PubMed

Ahangarpour, Akram; Oroojan, Ali Akbar; Khorsandi, Layasadat; Najimi, Seyedeh Asma

2017-04-01

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, D-galactose + VAC hydroalcoholic extract, aged, aged + VAC hydroalcoholic extract. The aged model was prepared by subcutaneous injection of D-galactose for 45 days and, VAC hydroalcoholic extract was gavaged twice a day in the last 7 days. 24 h after the last drug and extract administrations, serum samples and pancreatic tissues were removed to evaluate experimental and histological determinations. Serum glucose level decreased in VAC, D-galactose and, aged-treated groups compared to the control ( P < 0.05). Insulin level increased in VAC and decreased in D-galactose and aged VAC-treated mice compared to the control ( P < 0.05). Homeostasis model assessment-estimated insulin resistance (HOMA-IR) increased in D-galactose, aging, and VAC hydroalcoholic extract groups ( P < 0.05) and, administration of VAC hydroalcoholic extract improved HOMA-IR in D-galactose and aging treated animals. Despite the size of pancreatic islets decreased in aged and D-galactose groups, VAC administration recovered it. Present data showed that VAC hydroalcoholic extract has hypoglycemic and pancreatic protective effects in natural aged and aging model mice.

The oldest known primate skeleton and early haplorhine evolution.

PubMed

Ni, Xijun; Gebo, Daniel L; Dagosto, Marian; Meng, Jin; Tafforeau, Paul; Flynn, John J; Beard, K Christopher

2013-06-06

Reconstructing the earliest phases of primate evolution has been impeded by gaps in the fossil record, so that disagreements persist regarding the palaeobiology and phylogenetic relationships of the earliest primates. Here we report the discovery of a nearly complete and partly articulated skeleton of a primitive haplorhine primate from the early Eocene of China, about 55 million years ago, the oldest fossil primate of this quality ever recovered. Coupled with detailed morphological examination using propagation phase contrast X-ray synchrotron microtomography, our phylogenetic analysis based on total available evidence indicates that this fossil is the most basal known member of the tarsiiform clade. In addition to providing further support for an early dichotomy between the strepsirrhine and haplorhine clades, this new primate further constrains the age of divergence between tarsiiforms and anthropoids. It also strengthens the hypothesis that the earliest primates were probably diurnal, arboreal and primarily insectivorous mammals the size of modern pygmy mouse lemurs.

Poor embryo development in post-ovulatory in vivo-aged mouse oocytes is associated with mitochondrial dysfunction, but mitochondrial transfer from somatic cells is not sufficient for rejuvenation.

PubMed

Igarashi, Hideki; Takahashi, Toshifumi; Abe, Hiroyuki; Nakano, Hiroshi; Nakajima, Osamu; Nagase, Satoru

2016-10-01

Does in vivo aging of mouse oocytes affect mitochondrial function? Mitochondrial function was impaired in post-ovulatory in vivo-aged mouse oocytes and microinjection of somatic cell mitochondria did not rescue poor fertilization and embryonic development rates. The mechanisms underlying the decline in oocyte quality associated with oocyte aging remain unknown, although studies have suggested that the decline is regulated by mitochondrial dysfunction. However, only a limited number of studies have provided direct evidence implicating mitochondrial dysfunction in oocyte quality during the aging of oocytes. We used post-ovulatory, in vivo-aged mouse oocytes as a model for studying low-quality oocytes in oocyte aging. Superovulated oocytes released from the oviduct at 14 h and 20-24 h post-hCG injection were designated as 'fresh' and 'aged' oocytes, respectively. Membrane potentials and oxygen consumption in single oocytes were evaluated as measures of mitochondrial function in fresh and aged oocytes. Mitochondrial transcriptional factor A (TFAM) expression levels were examined by western blotting, and colocalization of mitochondria and TFAM was analyzed by measuring immunofluorescence in fresh and aged oocytes. IVF and blastocyst formation rates were calculated after oocyte microinjection with mitochondria derived from liver cells. The average mitochondrial membrane potential in fresh oocytes was significantly higher than that in aged oocytes (P < 0.05). The average oxygen consumption rate in aged oocytes was significantly lower than that in fresh oocytes (P < 0.05). Although total TFAM expression was unchanged, its colocalization with mitochondria decreased in aged oocytes. IVF and blastocyst formation rates for mitochondrion-injected aged oocytes were not significantly different from those for buffer-injected aged oocytes. Not applicable. A limitation of this study is that we did not examine the effects of microinjecting mitochondria from other somatic cell

Mechano growth factor, a splice variant of IGF-1, promotes neurogenesis in the aging mouse brain.

PubMed

Tang, Jason J; Podratz, Jewel L; Lange, Miranda; Scrable, Heidi J; Jang, Mi-Hyeon; Windebank, Anthony J

2017-07-07

Mechano growth factor (MGF) is a splice variant of IGF-1 first described in skeletal muscle. MGF induces muscle cell proliferation in response to muscle stress and injury. In control mice we found endogenous expression of MGF in neurogenic areas of the brain and these levels declined with age. To better understand the role of MGF in the brain, we used transgenic mice that constitutively overexpressed MGF from birth. MGF overexpression significantly increased the number of BrdU+ proliferative cells in the dentate gyrus (DG) of the hippocampus and subventricular zone (SVG). Although MGF overexpression increased the overall rate of adult hippocampal neurogenesis at the proliferation stage it did not alter the distribution of neurons at post-mitotic maturation stages. We then used the lac-operon system to conditionally overexpress MGF in the mouse brain beginning at 1, 3 and 12 months with histological and behavioral observation at 24 months of age. With conditional overexpression there was an increase of BrdU+ proliferating cells and BrdU+ differentiated mature neurons in the olfactory bulbs at 24 months when overexpression was induced from 1 and 3 months of age but not when started at 12 months. This was associated with preserved olfactory function. In vitro, MGF increased the size and number of neurospheres harvested from SVZ-derived neural stem cells (NSCs). These findings indicate that MGF overexpression increases the number of neural progenitor cells and promotes neurogenesis but does not alter the distribution of adult newborn neurons at post-mitotic stages. Maintaining youthful levels of MGF may be important in reversing age-related neuronal loss and brain dysfunction.

Changes of mitochondrial ultrastructure and function during ageing in mice and Drosophila.

PubMed

Brandt, Tobias; Mourier, Arnaud; Tain, Luke S; Partridge, Linda; Larsson, Nils-Göran; Kühlbrandt, Werner

2017-07-12

Ageing is a progressive decline of intrinsic physiological functions. We examined the impact of ageing on the ultrastructure and function of mitochondria in mouse and fruit flies ( Drosophila melanogaster ) by electron cryo-tomography and respirometry. We discovered distinct age-related changes in both model organisms. Mitochondrial function and ultrastructure are maintained in mouse heart, whereas subpopulations of mitochondria from mouse liver show age-related changes in membrane morphology. Subpopulations of mitochondria from young and old mouse kidney resemble those described for apoptosis. In aged flies, respiratory activity is compromised and the production of peroxide radicals is increased. In about 50% of mitochondria from old flies, the inner membrane organization breaks down. This establishes a clear link between inner membrane architecture and functional decline. Mitochondria were affected by ageing to very different extents, depending on the organism and possibly on the degree to which tissues within the same organism are protected against mitochondrial damage.

Inhibition of crystallin ascorbylation by nucleophilic compounds in the hSVCT2 mouse model of lenticular aging.

PubMed

Fan, Xingjun; Monnier, Vincent M

2008-11-01

Senile cataracts are associated with oxidation, fragmentation, cross-linking, insolubilization, and yellow pigmentation of lens crystallins. This process is partially explained by advanced glycation end products (AGEs) from ascorbic acid (ASA), as the authors unequivocally demonstrated in an hSVCT2 transgenic mouse. The authors present the first pharmacologic intervention study against ascorbylation in these mice. Five groups of mice from 2 to 9 months of age (10 mice/group) were fed a diet containing 0.1% (wt/wt) aminoguanidine, pyridoxamine, penicillamine, and nucleophilic compounds NC-I and NC-II. AGEs were determined in crystallin digests using high-performance liquid chromatography, liquid chromatography-mass spectrometry, or gas chromatography-mass spectrometry. Lens protein extract was incubated in vitro with ASA or dehydroascorbic acid. The ASA level increased approximately 10-fold in all groups and was unaffected by treatment. AGEs were increased several-fold in transgenic compared with control lenses. Body weight, food intake, lenticular glutathione, and glycated lysine level were unaltered. In vitro, all compounds inhibited AGE formation. In vivo, NC-I and NC-II significantly decreased protein fluorescence at lambda(ex)335/(em)385 (P = 0.045, P = 0.017, respectively) and lambda(ex)370/(em)440 (P = 0.029, P = 0.007, respectively). Other inhibitors had no effect. After 7 months, only NC-I and NC-II induced a 50% reduction in pentosidine (P = NS for NC-I; P = 0.035 for NC-II). NC-I also decreased carboxymethyllysine (P = 0.032) and carboxyethyllysine (P = NS). Fluorescent cross-link K2P was decreased by NC-I, NC-II, aminoguanidine, and pyridoxamine (P = NS). Pharmacologically blocking protein ascorbylation with absorbable guanidino compounds is feasible and may represent a new strategy for the delay of age-related nuclear sclerosis of the lens.

Dynamic activation of basilar membrane macrophages in response to chronic sensory cell degeneration in aging mouse cochleae

PubMed Central

Frye, Mitchell D.; Yang, Weiping; Zhang, Celia; Xiong, Binbin; Hu, Bo Hua

2016-01-01

In the sensory epithelium, macrophages have been identified on the scala tympani side of the basilar membrane. These basilar membrane macrophages are the spatially closest immune cells to sensory cells and are able to directly respond to and influence sensory cell pathogenesis. While basilar membrane macrophages have been studied in acute cochlear stresses, their behavior in response to chronic sensory cell degeneration is largely unknown. Here we report a systematic observation of the variance in phenotypes, the changes in morphology and distribution of basilar membrane tissue macrophages in different age groups of C57BL/6J mice, a mouse model of age-related sensory cell degeneration. This study reveals that mature, fully differentiated tissue macrophages, not recently infiltrated monocytes, are the major macrophage population for immune responses to chronic sensory cell death. These macrophages display dynamic changes in their numbers and morphologies as age increases, and the changes are related to the phases of sensory cell degeneration. Notably, macrophage activation precedes sensory cell pathogenesis, and strong macrophage activity is maintained until sensory cell degradation is complete. Collectively, these findings suggest that mature tissue macrophages on the basilar membrane are a dynamic group of cells that are capable of vigorous adaptation to changes in the local sensory epithelium environment influenced by sensory cell status. PMID:27837652

Dynamic activation of basilar membrane macrophages in response to chronic sensory cell degeneration in aging mouse cochleae.

PubMed

Frye, Mitchell D; Yang, Weiping; Zhang, Celia; Xiong, Binbin; Hu, Bo Hua

2017-02-01

In the sensory epithelium, macrophages have been identified on the scala tympani side of the basilar membrane. These basilar membrane macrophages are the spatially closest immune cells to sensory cells and are able to directly respond to and influence sensory cell pathogenesis. While basilar membrane macrophages have been studied in acute cochlear stresses, their behavior in response to chronic sensory cell degeneration is largely unknown. Here we report a systematic observation of the variance in phenotypes, the changes in morphology and distribution of basilar membrane tissue macrophages in different age groups of C57BL/6J mice, a mouse model of age-related sensory cell degeneration. This study reveals that mature, fully differentiated tissue macrophages, not recently infiltrated monocytes, are the major macrophage population for immune responses to chronic sensory cell death. These macrophages display dynamic changes in their numbers and morphologies as age increases, and the changes are related to the phases of sensory cell degeneration. Notably, macrophage activation precedes sensory cell pathogenesis, and strong macrophage activity is maintained until sensory cell degradation is complete. Collectively, these findings suggest that mature tissue macrophages on the basilar membrane are a dynamic group of cells that are capable of vigorous adaptation to changes in the local sensory epithelium environment influenced by sensory cell status. Copyright © 2016 Elsevier B.V. All rights reserved.

Effect of Fetal Mouse Lung Tissue Co-Culture on In Vitro Maturation of Mouse Immature Oocytes.

PubMed

Belbasi, Masomeh; Jorsaraei, Seyed Gholam Ali; Gholamitabar Tabari, Maryam; Khanbabaei, Ramzan

2017-10-01

The aim of this study was to evaluate the fetal mouse lung tissue co-culture on in vitro maturation (IVM) of mouse immature oocytes. In this experimental study, germinal vesicle (GV) oocytes from ovaries of a group of 25 female mice, 6-8 weeks of age, were dissected after being stimulated by 7.5 IU pregnant mare serum gonadotropin (PMSG) through an intraperitoneal (IP) injection. The fetal lung tissues were then prepared and cultured individually. A total number of 300 oocytes were cultured in the following three groups for 24 hours: control group (n=100) containing only base medium, group I (n=100) containing base medium co-cultured with 11.5- to 12.5-day old fetal mouse lung tissues, and group II (n=100) containing base medium co-cultured with 12.5- to 13.5-day old fetal mouse lung tissues. The proportion of GV and metaphase І (MI) oocytes matured into MІІ oocytes were compared among the three groups using analysis of variance (ANOVA). Correlation test were also used to evaluate the successful rate of IVM oocytes. The proportions of GV oocytes reaching MІІ stage were 46, 65, and 56%, in control, I and II groups, respectively (P<0.05). The percentage of the oocytes remaining at the GV stage were higher in control group as compared with two treatment groups (P<0.05). This study indicated that fetal mouse lung tissue co-culture method increased the percentage of GV oocytes reaching MII stage. Copyright© by Royan Institute. All rights reserved.

Paternal behavior and testosterone plasma levels in the Volcano Mouse Neotomodon alstoni (Rodentia: Muridae).

PubMed

Luis, Juana; Ramírez, Lorena; Carmona, Agustín; Ortiz, Guadalupe; Delgado, Jesús; Cárdenas, René

2009-01-01

Paternal behavior and testosterone plasma levels in the Volcano Mouse Neotomodon alstoni (Rodentia: Muridae). Although initially it was thought that testosterone inhibited the display of paternal behavior in males of rodents, it has been shown that in some species high testosterone levels are needed for exhibition of paternal care. In captivity, males of Volcano Mouse (Neotomodon alstoni) provide pups the same care provided by the mother, with the exception of suckling. Here we measured plasmatic testosterone concentrations 10 days after mating, five and 20 days postpartum, and 10 days after males were isolated from their families in order to determine possible changes in this hormone, associated to the presence and age of pups. Males of Volcano Mouse exhibited paternal behavior when their testosterone levels were relatively high. Although levels of this hormone did not change with the presence or pups age, males that invested more time in huddling showed higher testosterone levels. It is possible that in the Volcano Mouse testosterone modulates paternal behavior indirectly, as in the California mouse.

Detrusor expulsive strength is preserved, but responsiveness to bladder filling and urinary sensitivity is diminished in the aging mouse

PubMed Central

DeAngelis, Anthony; Kuchel, George A.

2012-01-01

The prevalence of urinary symptoms increases with age and is a significant source of distress, morbidity, and expense in the elderly. Recent evidence suggests that symptoms in the aged may result from sensory dysfunction, rather than abnormalities of detrusor performance. Therefore, we employed a pressure/flow multichannel urethane-anesthetized mouse cystometry model to test the hypothesis that in vivo detrusor performance does not degrade with aging. Secondarily, we sought to evaluate sensory responsiveness to volume using pressure-volume data generated during bladder filling. Cystometric data from 2-, 12-, 22-, and 26-mo-old female C57BL6 mice were compared. All 2- and 12-mo-old mice, 66% of 22-mo-old mice, and 50% of 26-mo-old mice responded to continuous bladder filling with periodic reflex voiding. Abdominal wall contraction with voiding had a minimal contribution to expulsive pressure, whereas compliance pressure was a significant contributor. Maximum bladder pressure, estimated detrusor pressure, detrusor impulse (pressure-time integral), as well as indices of detrusor power and work, did not decrease with aging. Bladder precontraction pressures decreased, compliance increased, and nonvoiding contraction counts did not change with increasing age. Intervoid intervals, per-void volumes, and voiding flow rates increased with age. Calculations approximating wall stress during filling suggested loss of bladder volume sensitivity with increasing age. We conclude that aging is associated with an impaired ability to respond to the challenge of continuous bladder filling with cyclic voiding, yet among responsive animals, voiding detrusor contraction strength does not degrade with aging in this murine model. Furthermore, indirect measures suggest that bladder volume sensitivity is diminished. Thus, changes in homeostatic reserve and peripheral and/or central sensory mechanisms may be important contributors to aging-associated changes in bladder function. PMID:22204955

The Mouse That Soared

NASA Astrophysics Data System (ADS)

2004-09-01

Astronomers have used an X-ray image to make the first detailed study of the behavior of high-energy particles around a fast moving pulsar. The image, from NASA's Chandra X-ray Observatory, shows the shock wave created as a pulsar plows supersonically through interstellar space. These results will provide insight into theories for the production of powerful winds of matter and antimatter by pulsars. Chandra's image of the glowing cloud, known as the Mouse, shows a stubby bright column of high-energy particles, about four light years in length, swept back by the pulsar's interaction with interstellar gas. The intense source at the head of the X-ray column is the pulsar, estimated to be moving through space at about 1.3 million miles per hour. VLA Radio Image of the Mouse, Full Field VLA Radio Image of the Mouse, Full Field A cone-shaped cloud of radio-wave-emitting particles envelopes the X-ray column. The Mouse, a.k.a. G359.23-0.82, was discovered in 1987 by radio astronomers using the National Science Foundation's Very Large Array in New Mexico. It gets its name from its appearance in radio images that show a compact snout, a bulbous body, and a remarkable long, narrow, tail that extends for about 55 light years. "A few dozen pulsar wind nebulae are known, including the spectacular Crab Nebula, but none have the Mouse's combination of relatively young age and incredibly rapid motion through interstellar space," said Bryan Gaensler of the Harvard-Smithsonian Center for Astrophysics and lead author of a paper on the Mouse that will appear in an upcoming issue of The Astrophysical Journal. "We effectively are seeing a supersonic cosmic wind tunnel, in which we can study the effects of a pulsar's motion on its pulsar wind nebula, and test current theories." Illustration of the Mouse System Illustration of the Mouse System Pulsars are known to be rapidly spinning, highly magnetized neutron stars -- objects so dense that a mass equal to that of the Sun is packed into a

Decreased adult hippocampal neurogenesis in the PDAPP mouse model of Alzheimer's disease.

PubMed

Donovan, Michael H; Yazdani, Umar; Norris, Rebekah D; Games, Dora; German, Dwight C; Eisch, Amelia J

2006-03-01

Abnormal subgranular zone (SGZ) neurogenesis is proposed to contribute to Alzheimer's disease (AD)-related decreases in hippocampal function. Our goal was to examine hippocampal neurogenesis in the PDAPP mouse, a model of AD with age-dependent accumulation of amyloid-beta(42) (Abeta(42))-containing plaques that is well studied with regard to AD therapies. A secondary goal was to determine whether altered neurogenesis in the PDAPP mouse is associated with abnormal maturation or number of mature cells. A tertiary goal was to provide insight into why hippocampal neurogenesis appears to be increased in AD post-mortem tissue and decreased in most AD mouse models. We report an age-dependent decrease in SGZ proliferation in homozygous PDAPP mice. At 1 year of age, PDAPP mice also had new dentate gyrus granule neurons with abnormal maturation and fewer dying cells relative to control mice. In contrast to decreased SGZ cell birth, PDAPP mice had increased birth of immature neurons in the outer portion of the granule cell layer (oGCL), providing insight into why some studies link AD with increased neurogenesis. However, these ectopic oGCL cells were still rare compared with SGZ proliferating cells, emphasizing that the primary characteristic of PDAPP mice is decreased neurogenesis. The decrease in SGZ neurogenesis was not associated with an age-dependent loss of dentate granule neurons. The altered neurogenesis in the PDAPP mouse may contribute to the age-related cognitive deficits reported in this model of AD and may be a useful adjunct target for assessing the impact of AD therapies. J. Comp. Neurol. 495:70-83, 2006. (c) 2006 Wiley-Liss, Inc.

Cognitive Performances Are Selectively Enhanced during Chronic Caloric Restriction or Resveratrol Supplementation in a Primate

PubMed Central

Marchal, Julia; Picq, Jean-Luc; Aujard, Fabienne

2011-01-01

Effects of an 18-month treatment with a moderate, chronic caloric restriction (CR) or an oral supplementation with resveratrol (RSV), a potential CR mimetic, on cognitive and motor performances were studied in non-human primates, grey mouse lemurs (Microcebus murinus). Thirty-three adult male mouse lemurs were assigned to three different groups: a control (CTL) group fed ad libitum, a CR group fed 70% of the CTL caloric intake, and an RSV group (RSV supplementation of 200 mg.kg−1.day−1) fed ad libitum. Three different cognitive tests, two motor tests, one emotional test and an analysis of cortisol level were performed in each group. Compared to CTL animals, CR or RSV animals did not show any change in motor performances evaluated by rotarod and jump tests, but an increase in spontaneous locomotor activity was observed in both groups. Working memory was improved by both treatments in the spontaneous alternation task. Despite a trend for CR group, only RSV supplementation increased spatial memory performances in the circular platform task. Finally, none of these treatments induced additional stress to the animals as reflected by similar results in the open field test and cortisol analyses compared to CTL animals. The present data provided the earliest evidence for a beneficial effect of CR or RSV supplementation on specific cognitive functions in a primate. Taken together, these results suggest that RSV could be a good candidate to mimic long-term CR effects and support the growing evidences that nutritional interventions can have beneficial effects on brain functions even in adults. PMID:21304942

Centralized mouse repositories.

PubMed

Donahue, Leah Rae; Hrabe de Angelis, Martin; Hagn, Michael; Franklin, Craig; Lloyd, K C Kent; Magnuson, Terry; McKerlie, Colin; Nakagata, Naomi; Obata, Yuichi; Read, Stuart; Wurst, Wolfgang; Hörlein, Andreas; Davisson, Muriel T

2012-10-01

Because the mouse is used so widely for biomedical research and the number of mouse models being generated is increasing rapidly, centralized repositories are essential if the valuable mouse strains and models that have been developed are to be securely preserved and fully exploited. Ensuring the ongoing availability of these mouse strains preserves the investment made in creating and characterizing them and creates a global resource of enormous value. The establishment of centralized mouse repositories around the world for distributing and archiving these resources has provided critical access to and preservation of these strains. This article describes the common and specialized activities provided by major mouse repositories around the world.

Glial molecular alterations with mouse brain development and aging: up-regulation of the Kir4.1 and aquaporin-4.

PubMed

Gupta, Rajaneesh Kumar; Kanungo, Madhusudan

2013-02-01

Glial cells, besides participating as passive supporting matrix, are also proposed to be involved in the optimization of the interstitial space for synaptic transmission by tight control of ionic and water homeostasis. In adult mouse brain, inwardly rectifying K+ (Kir4.1) and aquaporin-4 (AQP4) channels localize to astroglial endfeets in contact with brain microvessels and glutamate synapses, optimizing clearance of extracellular K(+) and water from the synaptic layers. However, it is still unclear whether there is an age-dependent difference in the expressions of Kir4.1 and AQP4 channels specifically during postnatal development and aging when various marked changes occur in brain and if these changes region specific. RT-PCR and immunoblotting was conducted to compare the relative expression of Kir4.1 and AQP4 mRNA and protein in the early and mature postnatal (0-, 15-, 45-day), adult (20-week), and old age (70-week) mice cerebral and cerebellar cortices. Expressions of Kir4.1 and AQP4 mRNA and protein are very low at 0-day. A pronounced and continuous increase was observed by mature postnatal ages (15-, 45-days). However, in the 70-week-old mice, expressions are significantly up-regulated as compared to 20-week-old mice. Both genes follow the same age-related pattern in both cerebral and cerebellar cortices. The time course and expression pattern suggests that Kir4.1 and AQP4 channels may play an important role in brain K(+) and water homeostasis in early postnatal weeks after birth and during aging.

Muscularity as a function of species, sex and age in small mammals

NASA Technical Reports Server (NTRS)

Pace, N.; Rahlmann, D. F.; Smith, A. H.

1984-01-01

Changes in the body skeletal muscle mass SMM (measured as a function of the ratio between the body creatine mass and the fat-free muscle creatine), and in muscularity (expressed as the ratio of SMM to fat-free body mass) were studied as functions of age, sex, and species in mouse, rat, hamster, guinea pig, and rabbit. Six animals of each sex were examined in eight age cohorts ranging from 1 to 24 months. Both species and age factors affect SMM. Strong sexual dimorphism in the SMM changes with age was displayed by mouse, rat, and guinea pig, whereas the hamster and rabbit were statistically monomorphic. The mouse, rat, and hamster attain a maximal SMM at about 1 year of age, whereas in the guinea pig and rabbit the decrease in SMM starts after 2 years. The value of muscularity reached a peak at age of 2-3 months in all animals of both sexes, with a pronounced difference among the species. The mouse emerged as the most muscular, while the guinea pig the least muscular, of all species.

Stem cell senescence drives age-attenuated induction of pituitary tumours in mouse models of paediatric craniopharyngioma.

PubMed

Mario Gonzalez-Meljem, Jose; Haston, Scott; Carreno, Gabriela; Apps, John R; Pozzi, Sara; Stache, Christina; Kaushal, Grace; Virasami, Alex; Panousopoulos, Leonidas; Neda Mousavy-Gharavy, Seyedeh; Guerrero, Ana; Rashid, Mamunur; Jani, Nital; Goding, Colin R; Jacques, Thomas S; Adams, David J; Gil, Jesus; Andoniadou, Cynthia L; Martinez-Barbera, Juan Pedro

2017-11-28

Senescent cells may promote tumour progression through the activation of a senescence-associated secretory phenotype (SASP), whether these cells are capable of initiating tumourigenesis in vivo is not known. Expression of oncogenic β-catenin in Sox2+ young adult pituitary stem cells leads to formation of clusters of stem cells and induction of tumours resembling human adamantinomatous craniopharyngioma (ACP), derived from Sox2- cells in a paracrine manner. Here, we uncover the mechanisms underlying this paracrine tumourigenesis. We show that expression of oncogenic β-catenin in Hesx1+ embryonic precursors also results in stem cell clusters and paracrine tumours. We reveal that human and mouse clusters are analogous and share a common signature of senescence and SASP. Finally, we show that mice with reduced senescence and SASP responses exhibit decreased tumour-inducing potential. Together, we provide evidence that senescence and a stem cell-associated SASP drive cell transformation and tumour initiation in vivo in an age-dependent fashion.

Fasting and Fast Food Diet Play an Opposite Role in Mice Brain Aging.

PubMed

Castrogiovanni, Paola; Li Volti, Giovanni; Sanfilippo, Cristina; Tibullo, Daniele; Galvano, Fabio; Vecchio, Michele; Avola, Roberto; Barbagallo, Ignazio; Malaguarnera, Lucia; Castorina, Sergio; Musumeci, Giuseppe; Imbesi, Rosa; Di Rosa, Michelino

2018-01-20

Fasting may be exploited as a possible strategy for prevention and treatment of several diseases such as diabetes, obesity, and aging. On the other hand, high-fat diet (HFD) represents a risk factor for several diseases and increased mortality. The aim of the present study was to evaluate the impact of fasting on mouse brain aging transcriptome and how HFD regulates such pathways. We used the NCBI Gene Expression Omnibus (GEO) database, in order to identify suitable microarray datasets comparing mouse brain transcriptome under fasting or HFD vs aged mouse brain transcriptome. Three microarray datasets were selected for this study, GSE24504, GSE6285, and GSE8150, and the principal molecular mechanisms involved in this process were evaluated. This analysis showed that, regardless of fasting duration, mouse brain significantly expressed 21 and 30 upregulated and downregulated genes, respectively. The involved biological processes were related to cell cycle arrest, cell death inhibition, and regulation of cellular metabolism. Comparing mouse brain transcriptome under fasting and aged conditions, we found out that the number of genes in common increased with the duration of fasting (222 genes), peaking at 72 h. In addition, mouse brain transcriptome under HFD resembles for the 30% the one of the aged mice. Furthermore, several molecular processes were found to be shared between HFD and aging. In conclusion, we suggest that fasting and HFD play an opposite role in brain transcriptome of aged mice. Therefore, an intermittent diet could represent a possible clinical strategy to counteract aging, loss of memory, and neuroinflammation. Furthermore, low-fat diet leads to the inactivation of brain degenerative processes triggered by aging.

Centralized Mouse Repositories

PubMed Central

Donahue, Leah Rae; de Angelis, Martin Hrabe; Hagn, Michael; Franklin, Craig; Lloyd, K. C. Kent; Magnuson, Terry; McKerlie, Colin; Nakagata, Naomi; Obata, Yuichi; Read, Stuart; Wurst, Wolfgang; Hörlein, Andreas; Davisson, Muriel T.

2013-01-01

Because the mouse is used so widely for biomedical research and the number of mouse models being generated is increasing rapidly, centralized repositories are essential if the valuable mouse strains and models that have been developed are to be securely preserved and fully exploited. Ensuring the ongoing availability of these mouse strains preserves the investment made in creating and characterizing them and creates a global resource of enormous value. The establishment of centralized mouse repositories around the world for distributing and archiving these resources has provided critical access to and preservation of these strains. This article describes the common and specialized activities provided by major mouse repositories around the world. PMID:22945696

MPHASYS: a mouse phenotype analysis system

PubMed Central

Calder, R Brent; Beems, Rudolf B; van Steeg, Harry; Mian, I Saira; Lohman, Paul HM; Vijg, Jan

2007-01-01

Background Systematic, high-throughput studies of mouse phenotypes have been hampered by the inability to analyze individual animal data from a multitude of sources in an integrated manner. Studies generally make comparisons at the level of genotype or treatment thereby excluding associations that may be subtle or involve compound phenotypes. Additionally, the lack of integrated, standardized ontologies and methodologies for data exchange has inhibited scientific collaboration and discovery. Results Here we introduce a Mouse Phenotype Analysis System (MPHASYS), a platform for integrating data generated by studies of mouse models of human biology and disease such as aging and cancer. This computational platform is designed to provide a standardized methodology for working with animal data; a framework for data entry, analysis and sharing; and ontologies and methodologies for ensuring accurate data capture. We describe the tools that currently comprise MPHASYS, primarily ones related to mouse pathology, and outline its use in a study of individual animal-specific patterns of multiple pathology in mice harboring a specific germline mutation in the DNA repair and transcription-specific gene Xpd. Conclusion MPHASYS is a system for analyzing multiple data types from individual animals. It provides a framework for developing data analysis applications, and tools for collecting and distributing high-quality data. The software is platform independent and freely available under an open-source license [1]. PMID:17553167

Reactivity of mouse antibodies against bromelain-treated mouse erythrocytes with thrombin-treated mouse platelets.

PubMed Central

Kawaguchi, S

1989-01-01

The reactivity of mouse antibodies against bromelain-treated mouse erythrocytes (BrMRBC) with mouse platelets before and after thrombin treatment was assessed by flow cytometry. Anti-BrMRBC antibodies could bind to thrombin-treated platelets, although normal platelets were also weakly reactive with the antibodies. The binding of anti-BrMRBC antibodies to platelets was confirmed by complement-dependent lysis. It is suggested that thrombin-activated platelets may be a real target for anti-BrMRBC antibodies. PMID:2467876

Genetic background influences age-related decline in visual and nonvisual retinal responses, circadian rhythms, and sleep☆

PubMed Central

Banks, Gareth; Heise, Ines; Starbuck, Becky; Osborne, Tamzin; Wisby, Laura; Potter, Paul; Jackson, Ian J.; Foster, Russell G.; Peirson, Stuart N.; Nolan, Patrick M.

2015-01-01

The circadian system is entrained to the environmental light/dark cycle via retinal photoreceptors and regulates numerous aspects of physiology and behavior, including sleep. These processes are all key factors in healthy aging showing a gradual decline with age. Despite their importance, the exact mechanisms underlying this decline are yet to be fully understood. One of the most effective tools we have to understand the genetic factors underlying these processes are genetically inbred mouse strains. The most commonly used reference mouse strain is C57BL/6J, but recently, resources such as the International Knockout Mouse Consortium have started producing large numbers of mouse mutant lines on a pure genetic background, C57BL/6N. Considering the substantial genetic diversity between mouse strains we expect there to be phenotypic differences, including differential effects of aging, in these and other strains. Such differences need to be characterized not only to establish how different mouse strains may model the aging process but also to understand how genetic background might modify age-related phenotypes. To ascertain the effects of aging on sleep/wake behavior, circadian rhythms, and light input and whether these effects are mouse strain-dependent, we have screened C57BL/6J, C57BL/6N, C3H-HeH, and C3H-Pde6b+ mouse strains at 5 ages throughout their life span. Our data show that sleep, circadian, and light input parameters are all disrupted by the aging process. Moreover, we have cataloged a number of strain-specific aging effects, including the rate of cataract development, decline in the pupillary light response, and changes in sleep fragmentation and the proportion of time spent asleep. PMID:25179226

Genetic background influences age-related decline in visual and nonvisual retinal responses, circadian rhythms, and sleep.

PubMed

Banks, Gareth; Heise, Ines; Starbuck, Becky; Osborne, Tamzin; Wisby, Laura; Potter, Paul; Jackson, Ian J; Foster, Russell G; Peirson, Stuart N; Nolan, Patrick M

2015-01-01

The circadian system is entrained to the environmental light/dark cycle via retinal photoreceptors and regulates numerous aspects of physiology and behavior, including sleep. These processes are all key factors in healthy aging showing a gradual decline with age. Despite their importance, the exact mechanisms underlying this decline are yet to be fully understood. One of the most effective tools we have to understand the genetic factors underlying these processes are genetically inbred mouse strains. The most commonly used reference mouse strain is C57BL/6J, but recently, resources such as the International Knockout Mouse Consortium have started producing large numbers of mouse mutant lines on a pure genetic background, C57BL/6N. Considering the substantial genetic diversity between mouse strains we expect there to be phenotypic differences, including differential effects of aging, in these and other strains. Such differences need to be characterized not only to establish how different mouse strains may model the aging process but also to understand how genetic background might modify age-related phenotypes. To ascertain the effects of aging on sleep/wake behavior, circadian rhythms, and light input and whether these effects are mouse strain-dependent, we have screened C57BL/6J, C57BL/6N, C3H-HeH, and C3H-Pde6b+ mouse strains at 5 ages throughout their life span. Our data show that sleep, circadian, and light input parameters are all disrupted by the aging process. Moreover, we have cataloged a number of strain-specific aging effects, including the rate of cataract development, decline in the pupillary light response, and changes in sleep fragmentation and the proportion of time spent asleep. Copyright © 2015 The Authors. Published by Elsevier Inc. All rights reserved.

The effect of supplementation with vitamin A on serum and liver concentrations in Puerto Rican crested toads (Peltophryne lemur) and its lack of impact on brown skin disease.

PubMed

Dutton, Christopher; Lentini, Andrew; Berkvens, Charlene; Crawshaw, Graham

2014-01-01

"Brown skin disease" (BSD) is a clinical syndrome of dysecdysis, chronic weight loss and death, previously reported in Puerto Rican crested toads (Peltophryne lemur). Although vitamin A deficiency has been suggested, its cause remains unknown and multiple treatments have failed to prevent or reverse the condition. This study compared the efficacy of vitamin A supplementation, administered in different forms and by different routes, in 48 captive born Puerto Rican crested toads fed from metamorphosis on gut-loaded, dusted, commercially raised crickets. Forty-five toads started to show clinical signs of BSD at 9 months of age; all toads were treated orally with an oil-based vitamin A formulation twice weekly for 2 months but continued to deteriorate. Two treatment groups were then compared: Animals in one group (n=19) received 2 IU injectable vitamin A (Aquasol-A) per gram bodyweight subcutaneously twice weekly for 3 months with no change in diet. Toads in the other group (n=22) received a single oral dose of vitamins A, D3 , and E, and were fed on earthworms and crickets gut-loaded with produce and a finely-ground alfalfa-based pellet, dusted with the same vitamin/mineral supplement. All affected animals developed severe BSD equally and died during, or were euthanized at the end of, the treatment regimen, with no clinical improvement. Animals supplemented with Aquasol-A had significantly higher liver vitamin A concentrations compared with the other treatment group, whereas serum retinol concentrations showed no significant difference. Vitamin A supplementation does not appear a successful treatment once BSD symptoms have developed. © 2014 Wiley Periodicals, Inc.

Losing grip: Senescent decline in physical strength in a small-bodied primate in captivity and in the wild.

PubMed

Hämäläinen, Anni; Dammhahn, Melanie; Aujard, Fabienne; Kraus, Cornelia

2015-01-01

Muscle strength reflects physical functioning, declines at old age and predicts health and survival in humans and laboratory animals. Age-associated muscle deterioration causes loss of strength and may impair fitness of wild animals. However, the effects of age and life-history characteristics on muscle strength in wild animals are unknown. We investigated environment- and sex-specific patterns of physical functioning by measuring grip strength in wild and captive gray mouse lemurs. We expected more pronounced strength senescence in captivity due to condition-dependent, extrinsic mortality found in nature. Males were predicted to be stronger but potentially experience more severe senescence than females as predicted by life history theory. We found similar senescent declines in captive males and females as well as wild females, whereas wild males showed little decline, presumably due to their early mortality. Captive animals were generally weaker and showed earlier declines than wild animals. Unexpectedly, females tended to be stronger than males, especially in the reproductive season. Universal intrinsic mechanisms (e.g. sarcopenia) likely cause the similar patterns of strength loss across settings. The female advantage in muscle strength merits further study; it may follow higher reproductive investment by males, or be an adaptation associated with female social dominance. Copyright © 2014 Elsevier Inc. All rights reserved.

Mouse Curve Biometrics

DOE Office of Scientific and Technical Information (OSTI.GOV)

Schulz, Douglas A.

2007-10-08

A biometric system suitable for validating user identity using only mouse movements and no specialized equipment is presented. Mouse curves (mouse movements with little or no pause between them) are individually classied and used to develop classication histograms, which are representative of an individual's typical mouse use. These classication histograms can then be compared to validate identity. This classication approach is suitable for providing continuous identity validation during an entire user session.

CircRNA accumulation in the aging mouse brain

PubMed Central

Gruner, Hannah; Cortés-López, Mariela; Cooper, Daphne A.; Bauer, Matthew; Miura, Pedro

2016-01-01

Circular RNAs (circRNAs) are a newly appreciated class of RNAs expressed across diverse phyla. These enigmatic transcripts are most commonly generated by back-splicing events from exons of protein-coding genes. This results in highly stable RNAs due to the lack of free 5′ and 3′ ends. CircRNAs are enriched in neural tissues, suggesting that they might have neural functions. Here, we sought to determine whether circRNA accumulation occurs during aging in mice. Total RNA-seq profiling of young (1 month old) and aged (22 month old) cortex, hippocampus and heart samples was performed. This led to the confident detection of 6,791 distinct circRNAs across these samples, including 675 novel circRNAs. Analysis uncovered a strong bias for circRNA upregulation during aging in neural tissues. These age-accumulation trends were verified for individual circRNAs by RT-qPCR and Northern analysis. In contrast, comparison of aged versus young hearts failed to reveal a global trend for circRNA upregulation. Age-accumulation of circRNAs in brain tissues was found to be largely independent from linear RNA expression of host genes. These findings suggest that circRNAs might play biological roles relevant to the aging nervous system. PMID:27958329

Assessing the use of immersive virtual reality, mouse and touchscreen in pointing and dragging-and-dropping tasks among young, middle-aged and older adults.

PubMed

Chen, Jiayin; Or, Calvin

2017-11-01

This study assessed the use of an immersive virtual reality (VR), a mouse and a touchscreen for one-directional pointing, multi-directional pointing, and dragging-and-dropping tasks involving targets of smaller and larger widths by young (n = 18; 18-30 years), middle-aged (n = 18; 40-55 years) and older adults (n = 18; 65-75 years). A three-way, mixed-factorial design was used for data collection. The dependent variables were the movement time required and the error rate. Our main findings were that the participants took more time and made more errors in using the VR input interface than in using the mouse or the touchscreen. This pattern applied in all three age groups in all tasks, except for multi-directional pointing with a larger target width among the older group. Overall, older adults took longer to complete the tasks and made more errors than young or middle-aged adults. Larger target widths yielded shorter movement times and lower error rates in pointing tasks, but larger targets yielded higher rates of error in dragging-and-dropping tasks. Our study indicated that any other virtual environments that are similar to those we tested may be more suitable for displaying scenes than for manipulating objects that are small and require fine control. Although interacting with VR is relatively difficult, especially for older adults, there is still potential for older adults to adapt to that interface. Furthermore, adjusting the width of objects according to the type of manipulation required might be an effective way to promote performance. Copyright © 2017 Elsevier Ltd. All rights reserved.

Mouse Cleaning Apparatus and Method

NASA Technical Reports Server (NTRS)

Williams, Glenn L. (Inventor)

2005-01-01

The method of using the mouse pad cleaning apparatus is disclosed and claimed. The method comprises the steps of uncovering the mouse cleaning surface, applying the mouse and ball of the mouse to the cleaning surface, moving the mouse in a rotational pattern on the mouse cleaning surface, removing the mouse form the mouse cleaning surface, washing the cleaning surface, and covering the mouse cleaning surface. A mouse pad cleaning apparatus comprising a plurality of substrates, each said substrate having adhesive thereon, said plurality of substrates residing in and affixed to a receptacle. A single substrate having adhesive, which may be washable or non-washable, thereon may be employed. The washable adhesive may be an organopolysiloxane or gelatinous elastomer.

Age-Dependent Long-Term Potentiation Deficits in the Prefrontal Cortex of the Fmr1 Knockout Mouse Model of Fragile X Syndrome.

PubMed

Martin, Henry G S; Lassalle, Olivier; Brown, Jonathan T; Manzoni, Olivier J

2016-05-01

The most common inherited monogenetic cause of intellectual disability is Fragile X syndrome (FXS). The clinical symptoms of FXS evolve with age during adulthood; however, neurophysiological data exploring this phenomenon are limited. The Fmr1 knockout (Fmr1KO) mouse models FXS, but studies in these mice of prefrontal cortex (PFC) function are underrepresented, and aging linked data are absent. We studied synaptic physiology and activity-dependent synaptic plasticity in the medial PFC of Fmr1KO mice from 2 to 12 months. In young adult Fmr1KO mice, NMDA receptor (NMDAR)-mediated long-term potentiation (LTP) is intact; however, in 12-month-old mice this LTP is impaired. In parallel, there was an increase in the AMPAR/NMDAR ratio and a concomitant decrease of synaptic NMDAR currents in 12-month-old Fmr1KO mice. We found that acute pharmacological blockade of mGlu5 receptor in 12-month-old Fmr1KO mice restored a normal AMPAR/NMDAR ratio and LTP. Taken together, the data reveal an age-dependent deficit in LTP in Fmr1KO mice, which may correlate to some of the complex age-related deficits in FXS. © The Author 2015. Published by Oxford University Press. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.

Glycogen synthase kinase-3 levels and phosphorylation undergo large fluctuations in mouse brain during development

PubMed Central

Beurel, Eléonore; Mines, Marjelo A; Song, Ling; Jope, Richard S

2012-01-01

Objectives Dysregulated glycogen synthase kinase-3 (GSK3) may contribute to the pathophysiology of mood disorders and other diseases, and appears to be a target of certain therapeutic drugs. The growing recognition of heightened vulnerability during development to many psychiatric diseases, including mood disorders, led us to test if there are developmental changes in mouse brain GSK3 and its regulation by phosphorylation and by therapeutic drugs. Methods GSK3 levels and phosphorylation were measured at seven ages of development in mouse cerebral cortex and hippocampus. Results Two periods of rapid transitions in GSK3 levels were identified, a large rise between postnatal day 1 and two to three weeks of age, where GSK3 levels were as high as four-fold adult mouse brain levels, and a rapid decline between two to four and eight weeks of age, when adult levels were reached. Inhibitory serine-phosphorylation of GSK3, particularly GSK3β, was extremely high in one-day postnatal mouse brain, and rapidly declined thereafter. These developmental changes in GSK3 were equivalent in male and female cerebral cortex, and differed from other signaling kinases, including Akt, ERK1/2, JNK, and p38 levels and phosphorylation. In contrast to adult mouse brain, where administration of lithium or fluoxetine rapidly and robustly increased serine-phosphorylation of GSK3, in young mice these responses were blunted or absent. Conclusions High brain levels of GSK3 and large fluctuations in its levels and phosphorylation in juvenile and adolescent mouse brain raise the possibility that they may contribute to destabilized mood regulation induced by environmental and genetic factors. PMID:23167932

Age-related pathology after adenoviral overexpression of the leucine-rich repeat kinase 2 in the mouse striatum.

PubMed

Kritzinger, Astrid; Ferger, Boris; Gillardon, Frank; Stierstorfer, Birgit; Birk, Gerald; Kochanek, Stefan; Ciossek, Thomas

2018-06-01

Mutations in leucine-rich repeat kinase 2 (LRRK2) age-dependently cause Parkinson's disease and are associated with several inflammatory diseases. So far, the potential role of LRRK2 expression in glial cells as mediators of neuroinflammation and the influence of aging have not been investigated in viral vector-based LRRK2 animal models. In this study, we compared the effect of striatal injection of high-capacity adenoviral vectors expressing either a kinase-overactive LRRK2 with the familial G2019S mutation or a kinase-inactive LRRK2 variant in young and old C57BL/6J mice. The intrinsic adenovirus tropism guided preferentially glial transduction, and the vector design led to stable expression for at least 6 months. In histopathological analysis, young mice expressing either LRRK2 variant presented with transient vacuolization of striatal white fiber tracts accompanied by accumulation of microglial cells and astrogliosis, but inflammation resolved without permanent damage. Old mice had a stronger and prolonged inflammatory reaction and experienced permanent damage in form of partial neuron loss after 3 months exclusively in case of LRRK2_G2019S expression. The autophagic receptor p62 accumulated in cells with high levels of either LRRK2 variant, even more so in old mice. We conclude that the aging mouse brain is more susceptible to LRRK2-associated pathology, and in this model, glial LRRK2 expression significantly contributed to neuroinflammation, ultimately causing neurodegeneration. Copyright © 2018 The Author(s). Published by Elsevier Inc. All rights reserved.

Metabolic drift in the aging brain.

PubMed

Ivanisevic, Julijana; Stauch, Kelly L; Petrascheck, Michael; Benton, H Paul; Epstein, Adrian A; Fang, Mingliang; Gorantla, Santhi; Tran, Minerva; Hoang, Linh; Kurczy, Michael E; Boska, Michael D; Gendelman, Howard E; Fox, Howard S; Siuzdak, Gary

2016-05-01

Brain function is highly dependent upon controlled energy metabolism whose loss heralds cognitive impairments. This is particularly notable in the aged individuals and in age-related neurodegenerative diseases. However, how metabolic homeostasis is disrupted in the aging brain is still poorly understood. Here we performed global, metabolomic and proteomic analyses across different anatomical regions of mouse brain at different stages of its adult lifespan. Interestingly, while severe proteomic imbalance was absent, global-untargeted metabolomics revealed an energymetabolic drift or significant imbalance in core metabolite levels in aged mouse brains. Metabolic imbalance was characterized by compromised cellular energy status (NAD decline, increased AMP/ATP, purine/pyrimidine accumulation) and significantly altered oxidative phosphorylation and nucleotide biosynthesis and degradation. The central energy metabolic drift suggests a failure of the cellular machinery to restore metabostasis (metabolite homeostasis) in the aged brain and therefore an inability to respond properly to external stimuli, likely driving the alterations in signaling activity and thus in neuronal function and communication.

Metabolic drift in the aging brain

PubMed Central

Ivanisevic, Julijana; Stauch, Kelly L.; Petrascheck, Michael; Benton, H. Paul; Epstein, Adrian A.; Fang, Mingliang; Gorantla, Santhi; Tran, Minerva; Hoang, Linh; Kurczy, Michael E.; Boska, Michael D.; Gendelman, Howard E.; Fox, Howard S.; Siuzdak, Gary

2016-01-01

Brain function is highly dependent upon controlled energy metabolism whose loss heralds cognitive impairments. This is particularly notable in the aged individuals and in age-related neurodegenerative diseases. However, how metabolic homeostasis is disrupted in the aging brain is still poorly understood. Here we performed global, metabolomic and proteomic analyses across different anatomical regions of mouse brain at different stages of its adult lifespan. Interestingly, while severe proteomic imbalance was absent, global-untargeted metabolomics revealed an energy metabolic drift or significant imbalance in core metabolite levels in aged mouse brains. Metabolic imbalance was characterized by compromised cellular energy status (NAD decline, increased AMP/ATP, purine/pyrimidine accumulation) and significantly altered oxidative phosphorylation and nucleotide biosynthesis and degradation. The central energy metabolic drift suggests a failure of the cellular machinery to restore metabostasis (metabolite homeostasis) in the aged brain and therefore an inability to respond properly to external stimuli, likely driving the alterations in signaling activity and thus in neuronal function and communication. PMID:27182841

Mouse phenotyping.

PubMed

Fuchs, Helmut; Gailus-Durner, Valérie; Adler, Thure; Aguilar-Pimentel, Juan Antonio; Becker, Lore; Calzada-Wack, Julia; Da Silva-Buttkus, Patricia; Neff, Frauke; Götz, Alexander; Hans, Wolfgang; Hölter, Sabine M; Horsch, Marion; Kastenmüller, Gabi; Kemter, Elisabeth; Lengger, Christoph; Maier, Holger; Matloka, Mikolaj; Möller, Gabriele; Naton, Beatrix; Prehn, Cornelia; Puk, Oliver; Rácz, Ildikó; Rathkolb, Birgit; Römisch-Margl, Werner; Rozman, Jan; Wang-Sattler, Rui; Schrewe, Anja; Stöger, Claudia; Tost, Monica; Adamski, Jerzy; Aigner, Bernhard; Beckers, Johannes; Behrendt, Heidrun; Busch, Dirk H; Esposito, Irene; Graw, Jochen; Illig, Thomas; Ivandic, Boris; Klingenspor, Martin; Klopstock, Thomas; Kremmer, Elisabeth; Mempel, Martin; Neschen, Susanne; Ollert, Markus; Schulz, Holger; Suhre, Karsten; Wolf, Eckhard; Wurst, Wolfgang; Zimmer, Andreas; Hrabě de Angelis, Martin

2011-02-01

Model organisms like the mouse are important tools to learn more about gene function in man. Within the last 20 years many mutant mouse lines have been generated by different methods such as ENU mutagenesis, constitutive and conditional knock-out approaches, knock-down, introduction of human genes, and knock-in techniques, thus creating models which mimic human conditions. Due to pleiotropic effects, one gene may have different functions in different organ systems or time points during development. Therefore mutant mouse lines have to be phenotyped comprehensively in a highly standardized manner to enable the detection of phenotypes which might otherwise remain hidden. The German Mouse Clinic (GMC) has been established at the Helmholtz Zentrum München as a phenotyping platform with open access to the scientific community (www.mousclinic.de; [1]). The GMC is a member of the EUMODIC consortium which created the European standard workflow EMPReSSslim for the systemic phenotyping of mouse models (http://www.eumodic.org/[2]). Copyright © 2010 Elsevier Inc. All rights reserved.

Effect of Age and Proteoglycan Deficiency on Collagen Fiber Re-Alignment and Mechanical Properties in Mouse Supraspinatus Tendon

PubMed Central

Connizzo, Brianne K.; Sarver, Joseph J.; Iozzo, Renato V.; Birk, David E.; Soslowsky, Louis J.

2013-01-01

Collagen fiber realignment is one mechanism by which tendon responds to load. Re-alignment is altered when the structure of tendon is altered, such as in the natural process of aging or with alterations of matrix proteins, such as proteoglycan expression. While changes in re-alignment and mechanical properties have been investigated recently during development, they have not been studied in (1) aged tendons, or (2) in the absence of key proteoglycans. Collagen fiber re-alignment and the corresponding mechanical properties are quantified throughout tensile mechanical testing in both the insertion site and the midsubstance of mouse supraspinatus tendons in wild type (WT), decorin-null (Dcn-/-), and biglycan-null (Bgn-/-) mice at three different ages (90 days, 300 days, and 570 days). Percent relaxation was significantly decreased with age in the WT and Dcn-/- tendons, but not in the Bgn-/- tendons. Changes with age were found in the linear modulus at the insertion site where the 300 day group was greater than the 90 day and 570 day group in the Bgn-/- tendons and the 90 day group was smaller than the 300 day and 570 day groups in the Dcn-/- tendons. However, no changes in modulus were found across age in WT tendons were found. The midsubstance fibers of the WT and Bgn-/- tendons were initially less aligned with increasing age. The re-alignment was significantly altered with age in the WT tendons, with older groups responding to load later in the mechanical test. This was also seen in the Dcn-/- midsubstance and the Bgn-/- insertion, but not in the other locations. Although some studies have found changes in the WT mechanical properties with age, this study did not support those findings. However, it did show fiber re-alignment changes at both locations with age, suggesting a breakdown of tendon′s ability to respond to load in later ages. In the proteoglycan-null tendons however, there were changes in the mechanical properties, accompanied only by

Refractive index measurement of the mouse crystalline lens using optical coherence tomography

PubMed Central

Chakraborty, Ranjay; Lacy, Kip D.; Tan, Christopher C.; Park, Han na; Pardue, Machelle T.

2014-01-01

In recent years, there has been a growing interest for using mouse models in refractive development and myopia research. The crystalline lens is a critical optical component of the mouse eye that occupies greater than 50% of the ocular space, and significant increases in thickness with age. However, changes in refractive index of the mouse crystalline lens are less known. In this study, we examined the changes in thickness and refractive index of the mouse crystalline lens for two different strains, wild-type (WT) and a nyx mutant (nob) over the course of normal visual development or after form deprivation. Refractive index and lens thickness measurements were made on ex vivo lens using spectral domain optical coherence tomography (SD-OCT). Comparison of refractive index measurements on 5 standard ball lenses using the SD-OCT and their known refractive indices (manufacturer provided) indicated good precision (intra-class correlation coefficient, 0.998 and Bland-Altman coefficient of repeatability, 0.116) of the SD-OCT to calculate mouse lens refractive index ex vivo. During normal visual development, lens thickness increased significantly with age for three different cohorts of mice, aged 4 (average thickness from both eyes; WT: 1.78 ± 0.03, nob: 1.79 ± 0.08 mm), 10 (WT: 2.02 ± 0.05, nob: 2.01 ± 0.04 mm) and 16 weeks (WT: 2.12 ± 0.06, nob: 2.09 ± 0.06 mm, p<0.001). Lens thickness was not significantly different between the two strains at any age (p=0.557). For mice with normal vision, refractive index for isolated crystalline lenses in nob mice was significantly greater than WT mice (mean for all ages; WT: 1.42 ± 0.01, nob: 1.44 ± 0.001, p<0.001). After 4 weeks of form deprivation to the right eye using a skull-mounted goggling apparatus, a thinning of the crystalline lens was observed in both right and left eyes of goggled animals compared to their naïve controls (average from both the right and the left eye) for both strains (p=0.052). In form deprived

Comparative analysis of genome maintenance genes in naked mole rat, mouse, and human.

PubMed

MacRae, Sheila L; Zhang, Quanwei; Lemetre, Christophe; Seim, Inge; Calder, Robert B; Hoeijmakers, Jan; Suh, Yousin; Gladyshev, Vadim N; Seluanov, Andrei; Gorbunova, Vera; Vijg, Jan; Zhang, Zhengdong D

2015-04-01

Genome maintenance (GM) is an essential defense system against aging and cancer, as both are characterized by increased genome instability. Here, we compared the copy number variation and mutation rate of 518 GM-associated genes in the naked mole rat (NMR), mouse, and human genomes. GM genes appeared to be strongly conserved, with copy number variation in only four genes. Interestingly, we found NMR to have a higher copy number of CEBPG, a regulator of DNA repair, and TINF2, a protector of telomere integrity. NMR, as well as human, was also found to have a lower rate of germline nucleotide substitution than the mouse. Together, the data suggest that the long-lived NMR, as well as human, has more robust GM than mouse and identifies new targets for the analysis of the exceptional longevity of the NMR. © 2015 The Authors. Aging Cell published by the Anatomical Society and John Wiley & Sons Ltd.

A roadmap for the genetic analysis of renal aging

PubMed Central

Noordmans, Gerda A; Hillebrands, Jan-Luuk; van Goor, Harry; Korstanje, Ron

2015-01-01

Several studies show evidence for the genetic basis of renal disease, which renders some individuals more prone than others to accelerated renal aging. Studying the genetics of renal aging can help us to identify genes involved in this process and to unravel the underlying pathways. First, this opinion article will give an overview of the phenotypes that can be observed in age-related kidney disease. Accurate phenotyping is essential in performing genetic analysis. For kidney aging, this could include both functional and structural changes. Subsequently, this article reviews the studies that report on candidate genes associated with renal aging in humans and mice. Several loci or candidate genes have been found associated with kidney disease, but identification of the specific genetic variants involved has proven to be difficult. CUBN, UMOD, and SHROOM3 were identified by human GWAS as being associated with albuminuria, kidney function, and chronic kidney disease (CKD). These are promising examples of genes that could be involved in renal aging, and were further mechanistically evaluated in animal models. Eventually, we will provide approaches for performing genetic analysis. We should leverage the power of mouse models, as testing in humans is limited. Mouse and other animal models can be used to explain the underlying biological mechanisms of genes and loci identified by human GWAS. Furthermore, mouse models can be used to identify genetic variants associated with age-associated histological changes, of which Far2, Wisp2, and Esrrg are examples. A new outbred mouse population with high genetic diversity will facilitate the identification of genes associated with renal aging by enabling high-resolution genetic mapping while also allowing the control of environmental factors, and by enabling access to renal tissues at specific time points for histology, proteomics, and gene expression. PMID:26219736

How long will my mouse live? Machine learning approaches for prediction of mouse life span.

PubMed

Swindell, William R; Harper, James M; Miller, Richard A

2008-09-01

Prediction of individual life span based on characteristics evaluated at middle-age represents a challenging objective for aging research. In this study, we used machine learning algorithms to construct models that predict life span in a stock of genetically heterogeneous mice. Life-span prediction accuracy of 22 algorithms was evaluated using a cross-validation approach, in which models were trained and tested with distinct subsets of data. Using a combination of body weight and T-cell subset measures evaluated before 2 years of age, we show that the life-span quartile to which an individual mouse belongs can be predicted with an accuracy of 35.3% (+/-0.10%). This result provides a new benchmark for the development of life-span-predictive models, but improvement can be expected through identification of new predictor variables and development of computational approaches. Future work in this direction can provide tools for aging research and will shed light on associations between phenotypic traits and longevity.

The development of inter-strain variation in cortical and trabecular traits during growth of the mouse lumbar vertebral body.

PubMed

Ramcharan, M A; Faillace, M E; Guengerich, Z; Williams, V A; Jepsen, K J

2017-03-01

How cortical and trabecular bone co-develop to establish a mechanically functional structure is not well understood. Comparing early postnatal differences in morphology of lumbar vertebral bodies for three inbred mouse strains identified coordinated changes within and between cortical and trabecular traits. These early coordinate changes defined the phenotypic differences among the inbred mouse strains. Age-related changes in cortical and trabecular traits have been well studied; however, very little is known about how these bone tissues co-develop from day 1 of postnatal growth to establish functional structures by adulthood. In this study, we aimed to establish how cortical and trabecular tissues within the lumbar vertebral body change during growth for three inbred mouse strains that express wide variation in adult bone structure and function. Bone traits were quantified for lumbar vertebral bodies of female A/J, C57BL/6J (B6), and C3H/HeJ (C3H) inbred mouse strains from 1 to 105 days of age (n = 6-10 mice/age/strain). Inter-strain differences in external bone size were observed as early as 1 day of age. Reciprocal and rapid changes in the trabecular bone volume fraction and alignment in the direction of axial compression were observed by 7 days of age. Importantly, the inter-strain difference in adult trabecular bone volume fraction was established by 7 days of age. Early variation in external bone size and trabecular architecture was followed by progressive increases in cortical area between 28 and 105 days of age, with the greatest increases in cortical area seen in the mouse strain with the lowest trabecular mass. Establishing the temporal changes in bone morphology for three inbred mouse strains revealed that genetic variation in adult trabecular traits were established early in postnatal development. Early variation in trabecular architecture preceded strain-specific increases in cortical area and changes in cortical thickness. This study

The BALB/c mouse: Effect of standard vivarium lighting on retinal pathology during aging

PubMed Central

Bell, Brent A.; Kaul, Charles; Bonilha, Vera L.; Rayborn, Mary E.; Shadrach, Karen; Hollyfield, Joe G.

2015-01-01

intensity of illumination of the groups. Advanced age and top row illuminance conditions resulted in significant photoreceptor cell loss as judged by decreased thickness of the ONL. Photoreceptor loss was preceded by both retinal infoldings and the presence of autofluorescent inflammatory cells in the outer retina, suggesting that these changes are early indicators of light toxicity in the BALB/cJ mouse. PMID:25895728

Second-Generation Six-Limbed Experimental Robot

NASA Technical Reports Server (NTRS)

Kennedy, Brett; Okon, Avi; Aghazarian, Hrand; Robinson, Matthew; Garrett, Michael; Magnone, Lee

2004-01-01

The figure shows the LEMUR II - the second generation of the Limbed Excursion Mechanical Utility Robot (LEMUR), which was described in "Six-Legged Experimental Robot" (NPO-20897), NASA Tech Briefs, Vol. 25, No. 12 (December 2001), page 58. The LEMUR II incorporates a number of improvements, including new features, that extend its capabilities beyond those of its predecessor, which is now denoted the LEMUR I. To recapitulate: the LEMUR I was a six-limbed robot for demonstrating robotic capabilities for assembly, maintenance, and inspection. The LEMUR I was designed to be capable of walking autonomously along a truss structure toward a mechanical assembly at a prescribed location and to perform other operations. The LEMUR I was equipped with stereoscopic video cameras and image-data-processing circuitry for navigation and mechanical operations. It was also equipped with a wireless modem, through which it could be commanded remotely. Upon arrival at a mechanical assembly, the LEMUR I would perform simple mechanical operations with one or both of its front limbs. It could also transmit images to a host computer. Each of the six limbs of the LEMUR I was operated independently. Each of the four rear limbs had three degrees of freedom (DOFs), while each of the front two limbs had four DOFs. The front two limbs were designed to hold, operate, and/or be integrated with tools. The LEMUR I included an onboard computer equipped with an assortment of digital control circuits, digital input/output circuits, analog-to-digital converters for input, and digital-to-analog (D/A) converters for output. Feedback from optical encoders in the limb actuators was utilized for closed-loop microcomputer control of the positions and velocities of the actuators. The LEMUR II incorporates the following improvements over the LEMUR I: a) The drive trains for the joints of the LEMUR II are more sophisticated, providing greater torque and accuracy. b) The six limbs are arranged symmetrically about

Factors affecting computer mouse use for young children: implications for AAC.

PubMed

Costigan, F Aileen; Light, Janice C; Newell, Karl M

2012-06-01

More than 12% of preschoolers receiving special education services have complex communication needs, including increasing numbers of children who do not have significant motor impairments (e.g., children with autism spectrum disorders, Down syndrome, etc.). In order to meet their diverse communication needs (e.g., face-to-face, written, Internet, telecommunication), these children may use mainstream technologies accessed via the mouse, yet little is known about factors that affect the mouse performance of young children. This study used a mixed factorial design to investigate the effects of age, target size, and angle of approach on accuracy and time required for accurate target selection with a mouse for 20 3-year-old and 20 4-year-old children. The 4-year-olds were generally more accurate and faster than the 3-year-olds. Target size and angle mediated differences in performance within age groups. The 3-year-olds were more accurate and faster in selecting the medium and large targets relative to the small target, were faster in selecting the large relative to the medium target, and were faster in selecting targets along the vertical relative to the diagonal angle. The 4-year-olds were faster in selecting the medium and large targets relative to the small target. Implications for improving access to AAC include the preliminary suggestion of age-related threshold target sizes that support sufficient accuracy, the possibility of efficiency benefits when target size is increased up to an age-related threshold, and identification of the potential utility of the vertical angle as a context for training navigational input device use.

Metformin prevents methylglyoxal-induced apoptosis of mouse Schwann cells

DOE Office of Scientific and Technical Information (OSTI.GOV)

Ota, Kimiko; Nakamura, Jiro; Li, Weiguo

2007-05-25

Methylglyoxal (MG) is involved in the pathogenesis of diabetic complications via the formation of advanced glycation end products (AGEs) and reactive oxygen species (ROS). To clarify whether the antidiabetic drug metformin prevents Schwann cell damage induced by MG, we cultured mouse Schwann cells in the presence of MG and metformin. Cell apoptosis was evaluated using Hoechst 33342 nuclear staining, caspase-3 activity, and c-Jun-N-terminal kinase (JNK) phosphorylation. Intracellular ROS formation was determined by flow cytometry, and AMP-activated kinase (AMPK) phosphorylation was also examined. MG treatment resulted in blunted cell proliferation, an increase in the number of apoptotic cells, and the activationmore » of caspase-3 and JNK along with enhanced intracellular ROS formation. All of these changes were significantly inhibited by metformin. No significant activation of AMPK by MG or metformin was observed. Taken together, metformin likely prevents MG-induced apoptotic signals in mouse Schwann cells by inhibiting the formation of AGEs and ROS.« less

Preservation of Cognitive Function by Lepidium meyenii (Maca) Is Associated with Improvement of Mitochondrial Activity and Upregulation of Autophagy-Related Proteins in Middle-Aged Mouse Cortex

PubMed Central

Guo, Shan-Shan; Gao, Xiao-Fang; Gu, Yan-Rong

2016-01-01

Maca has been used as a foodstuff and a traditional medicine in the Andean region for over 2,000 years. Recently the neuroprotective effects of maca also arouse interest of researchers. Decrease in mitochondrial function and decline in autophagy signaling may participate in the process of age-related cognitive decline. This study aimed to investigate if maca could improve cognitive function of middle-aged mice and if this effect was associated with improvement of mitochondrial activity and modulation of autophagy signaling in mouse cortex. Fourteen-month-old male ICR mice received maca powder administered by gavage for five weeks. Maca improved cognitive function, motor coordination, and endurance capacity in middle-aged mice, accompanied by increased mitochondrial respiratory function and upregulation of autophagy-related proteins in cortex. Our findings suggest that maca is a newly defined nutritional plant which can improve mitochondrial function and upregulate autophagy-related proteins and may be an effective functional food for slowing down age-related cognitive decline. PMID:27648102

Preservation of Cognitive Function by Lepidium meyenii (Maca) Is Associated with Improvement of Mitochondrial Activity and Upregulation of Autophagy-Related Proteins in Middle-Aged Mouse Cortex.

PubMed

Guo, Shan-Shan; Gao, Xiao-Fang; Gu, Yan-Rong; Wan, Zhong-Xiao; Lu, A-Ming; Qin, Zheng-Hong; Luo, Li

2016-01-01

Maca has been used as a foodstuff and a traditional medicine in the Andean region for over 2,000 years. Recently the neuroprotective effects of maca also arouse interest of researchers. Decrease in mitochondrial function and decline in autophagy signaling may participate in the process of age-related cognitive decline. This study aimed to investigate if maca could improve cognitive function of middle-aged mice and if this effect was associated with improvement of mitochondrial activity and modulation of autophagy signaling in mouse cortex. Fourteen-month-old male ICR mice received maca powder administered by gavage for five weeks. Maca improved cognitive function, motor coordination, and endurance capacity in middle-aged mice, accompanied by increased mitochondrial respiratory function and upregulation of autophagy-related proteins in cortex. Our findings suggest that maca is a newly defined nutritional plant which can improve mitochondrial function and upregulate autophagy-related proteins and may be an effective functional food for slowing down age-related cognitive decline.

In vivo characterization of a bigenic fluorescent mouse model of Alzheimer's disease with neurodegeneration.

PubMed

Crowe, Sarah E; Ellis-Davies, Graham C R

2013-07-01

The loss of cognitive function in Alzheimer's disease (AD) patients is strongly correlated with the loss of neurons in various regions of the brain. We have created a new fluorescent bigenic mouse model of AD by crossing "H-line" yellow fluorescent protein (YFP) mice with the 5xFAD mouse model, which we call the 5XY mouse model. The 5xFAD mouse has been shown to have significant loss of L5 pyramidal neurons by 12 months of age. These neurons are transgenically labeled with YFP in the 5XY mouse, which enable longitudinal imaging of structural changes. In the 5XY mice, we observed an appearance of axonal dystrophies, with two distinct morphologies in the early stages of the disease progression. Simple swelling dystrophies are transient in nature and are not directly associated with amyloid plaques. Rosette dystrophies are more complex structures that remained stable throughout all imaging sessions, and always surrounded an amyloid plaque. Plaque growth was followed over 4 weeks, and significant growth was seen between weekly imaging sessions. In addition to axonal dystrophy appearance and plaque growth, we were able to follow spine stability in 4-month old 5XY mice, which revealed no significant loss of spines. 5XY mice also showed a striking shrinkage of the neocortex at older ages (12-14 months). The 5XY mouse model may be a valuable tool for studying specific events in the degeneration of the neocortex, and may suggest new avenues for therapeutic intervention. Copyright © 2013 Wiley Periodicals, Inc.

Postovulatory aging affects dynamics of mRNA, expression and localization of maternal effect proteins, spindle integrity and pericentromeric proteins in mouse oocytes

PubMed Central

Trapphoff, T.; Heiligentag, M.; Dankert, D.; Demond, H.; Deutsch, D.; Fröhlich, T.; Arnold, G.J.; Grümmer, R.; Horsthemke, B.; Eichenlaub-Ritter, U.

2016-01-01

ATRX or X-linked nuclear protein (XNP)). For proteome analysis five replicates of 30 mouse oocytes were analyzed by selected reaction monitoring (SRM). MATERIAL AND METHODS GV and MII oocytes were obtained from large antral follicles or ampullae of sexually mature mice, respectively. Denuded MII oocytes were aged for 24 h post ovulation. For analysis of distribution and abundance of polyadenylated RNAs fixed oocytes were in situ hybridized to Cy5 labeled oligo(dT)20 nucleotides. Absolute quantification of protein concentration per oocyte of selected proteins was done by SRM proteome analysis. Relative abundance of ATRX was assessed by confocal laser scanning microscopy (CLSM) of whole mount formaldehyde fixed oocytes or after removal of zona and spreading. MSY2 protein distribution and abundance was studied in MII oocytes prior to, during and after exposure to nocodazole, or after aging for 2 h in presence of H2O2 or for 24 h in presence of a glutathione donor, glutathione ethylester (GEE). MAIN RESULTS AND ROLE OF CHANCE The significant reduction in abundance of proteins (P < 0.001) translated from maternal mRNAs was independent of polyadenylation status, while their protein localization was not significantly changed by aging. Most of other proteins quantified by SRM analysis did not significantly change in abundance upon aging except MSY2 and GTSF1. MSY2 was enriched in the subcortical RNP domain (SCRD) and in the spindle chromosome complex (SCC) in a distinct pattern, right and left to the chromosomes. There was a significant loss of MSY2 from the SCRD (P < 0.001) and the spindle after postovulatory aging. Microtubule de- and repolymerization caused reversible loss of MSY2 spindle-association whereas H2O2 stress did not significantly decrease MSY2 abundance. Aging in presence of GEE decreased significantly (P < 0.05) the aging-related overall and cytoplasmic loss of MSY2. Postovulatory aging increased significantly spindle abnormalities, unaligned chromosomes, and

Postovulatory aging affects dynamics of mRNA, expression and localization of maternal effect proteins, spindle integrity and pericentromeric proteins in mouse oocytes.

PubMed

Trapphoff, T; Heiligentag, M; Dankert, D; Demond, H; Deutsch, D; Fröhlich, T; Arnold, G J; Grümmer, R; Horsthemke, B; Eichenlaub-Ritter, U

2016-01-01

Is the postovulatory aging-dependent differential decrease of mRNAs and polyadenylation of mRNAs coded by maternal effect genes associated with altered abundance and distribution of maternal effect and RNA-binding proteins (MSY2)? Postovulatory aging results in differential reduction in abundance of maternal effect proteins, loss of RNA-binding proteins from specific cytoplasmic domains and critical alterations of pericentromeric proteins without globally affecting protein abundance. Oocyte postovulatory aging is associated with differential alteration in polyadenylation and reduction in abundance of mRNAs coded by selected maternal effect genes. RNA-binding and -processing proteins are involved in storage, polyadenylation and degradation of mRNAs thus regulating stage-specific recruitment of maternal mRNAs, while chromosomal proteins that are stage-specifically expressed at pericentromeres, contribute to control of chromosome segregation and regulation of gene expression in the zygote. Germinal vesicle (GV) and metaphase II (MII) oocytes from sexually mature C57B1/6J female mice were investigated. Denuded in vivo or in vitro matured MII oocytes were postovulatory aged and analyzed by semiquantitative confocal microscopy for abundance and localization of polyadenylated RNAs, proteins of maternal effect genes (transcription activator BRG1 also known as ATP-dependent helicase SWI/SNF related, matrix associated, actin dependent regulator of chromatin, subfamily a, member 4 (SMARCA4) and NOD-like receptor family pyrin domain containing 5 (NLRP5) also known as MATER), RNA-binding proteins (MSY2 also known as germ cell-specific Y-box-binding protein, YBX2), and post-transcriptionally modified histones (trimethylated histone H3K9 and acetylated histone H4K12), as well as pericentromeric ATRX (alpha thalassemia/mental retardation syndrome X-linked, also termed ATP-dependent helicase ATRX or X-linked nuclear protein (XNP)). For proteome analysis five replicates of 30 mouse

Shared Ageing Research Models (ShARM): a new facility to support ageing research.

PubMed

Duran, Adele L; Potter, Paul; Wells, Sara; Kirkwood, Tom; von Zglinicki, Thomas; McArdle, Anne; Scudamore, Cheryl; Meng, Qing-Jun; de Haan, Gerald; Corcoran, Anne; Bellantuono, Ilaria

2013-12-01

In order to manage the rise in life expectancy and the concomitant increased occurrence of age-related diseases, research into ageing has become a strategic priority. Mouse models are commonly utilised as they share high homology with humans and show many similar signs and diseases of ageing. However, the time and cost needed to rear aged cohorts can limit research opportunities. Sharing of resources can provide an ethically and economically superior framework to overcome some of these issues but requires dedicated infrastructure. Shared Ageing Research Models (ShARM) ( www.ShARMUK.org ) is a new, not-for-profit organisation funded by Wellcome Trust, open to all investigators. It collects, stores and distributes flash frozen tissues from aged murine models through its biorepository and provides a database of live ageing mouse colonies available in the UK and abroad. It also has an online environment (MICEspace) for collation and analysis of data from communal models and discussion boards on subjects such as the welfare of ageing animals and common endpoints for intervention studies. Since launching in July 2012, thanks to the generosity of researchers in UK and Europe, ShARM has collected more than 2,500 tissues and has in excess of 2,000 mice registered in live ageing colonies. By providing the appropriate support, ShARM has been able to bring together the knowledge and experience of investigators in the UK and Europe to maximise research outputs with little additional cost and minimising animal use in order to facilitate progress in ageing research.

The effect of habitat disturbance on the abundance of nocturnal lemur species on the Masoala Peninsula, northeastern Madagascar.

PubMed

Sawyer, Rachel Mary; Fenosoa, Zo Samuel Ella; Andrianarimisa, Aristide; Donati, Giuseppe

2017-01-01

Madagascar is one of the world's biodiversity hotspots. The island's past and current rates of deforestation and habitat disturbance threaten its plethora of endemic biodiversity. On Madagascar, tavy (slash and burn agriculture), land conversion for rice cultivation, illegal hardwood logging and bushmeat hunting are the major contributors to habitat disturbance. Understanding species-specific responses to habitat disturbance across different habitat types is crucial when designing conservation strategies. We surveyed three nocturnal lemur species in four forest types of varying habitat disturbance on the Masoala Peninsula, northeastern Madagascar. We present here updated abundance and density estimates for the Endangered Avahi mooreorum and Lepilemur scottorum, and Microcebus sp. Distance sampling surveys were conducted on 11 transects, covering a total of 33 km after repeated transect walks. We collected data on tree height, bole height, diameter at breast height, canopy cover and tree density using point-quarter sampling to characterise the four forest types (primary lowland, primary littoral, selectively logged and agricultural mosaic). Median encounter rates by forest type ranged from 1 to 1.5 individuals (ind.)/km (Microcebus sp.), 0-1 ind./km (A. mooreorum) and 0-1 ind./km (L. scottorum). Species density estimates were calculated at 232.31 ind./km 2 (Microcebus sp.) and 121.21 ind./km 2 (A. mooreorum), while no density estimate is provided for L. scottorum due to a small sample size. Microcebus sp. was most tolerant to habitat disturbance, exhibiting no significant effect of forest type on abundance. Its small body size, omnivorous diet and generalised locomotion appear to allow it to tolerate a variety of habitat disturbance. Both A. mooreorum and L. scottorum showed significant effects of forest type on their respective abundance. This study suggests that the specialist locomotion and diet of A. mooreorum and L. scottorum make them susceptible to the

Diverse Application of Magnetic Resonance Imaging for Mouse Phenotyping

PubMed Central

Wu, Yijen L.; Lo, Cecilia W.

2017-01-01

Small animal models, particularly mouse models, of human diseases are becoming an indispensable tool for biomedical research. Studies in animal models have provided important insights into the etiology of diseases and accelerated the development of therapeutic strategies. Detailed phenotypic characterization is essential, both for the development of such animal models and mechanistic studies into disease pathogenesis and testing the efficacy of experimental therapeutics. Magnetic Resonance Imaging (MRI) is a versatile and non-invasive imaging modality with excellent penetration depth, tissue coverage, and soft tissue contrast. MRI, being a multi-modal imaging modality, together with proven imaging protocols and availability of good contrast agents, is ideally suited for phenotyping mutant mouse models. Here we describe the applications of MRI for phenotyping structural birth defects involving the brain, heart, and kidney in mice. The versatility of MRI and its ease of use are well suited to meet the rapidly increasing demands for mouse phenotyping in the coming age of functional genomics. PMID:28544650

The effects of ageing on mouse muscle microstructure: a comparative study of time-dependent diffusion MRI and histological assessment.

PubMed

Porcari, Paola; Hall, Matt G; Clark, Chris A; Greally, Elizabeth; Straub, Volker; Blamire, Andrew M

2018-03-01

The investigation of age-related changes in muscle microstructure between developmental and healthy adult mice may help us to understand the clinical features of early-onset muscle diseases, such as Duchenne muscular dystrophy. We investigated the evolution of mouse hind-limb muscle microstructure using diffusion imaging of in vivo and in vitro samples from both actively growing and mature mice. Mean apparent diffusion coefficients (ADCs) of the gastrocnemius and tibialis anterior muscles were determined as a function of diffusion time (Δ), age (7.5, 22 and 44 weeks) and diffusion gradient direction, applied parallel or transverse to the principal axis of the muscle fibres. We investigated a wide range of diffusion times with the goal of probing a range of diffusion lengths characteristic of muscle microstructure. We compared the diffusion time-dependent ADC of hind-limb muscles with histology. ADC was found to vary as a function of diffusion time in muscles at all stages of maturation. Muscle water diffusivity was higher in younger (7.5 weeks) than in adult (22 and 44 weeks) mice, whereas no differences were observed between the older ages. In vitro data showed the same diffusivity pattern as in vivo data. The highlighted differences in diffusion properties between young and mature muscles suggested differences in underlying muscle microstructure, which were confirmed by histological assessment. In particular, although diffusion was more restricted in older muscle, muscle fibre size increased significantly from young to adult age. The extracellular space decreased with age by only ~1%. This suggests that the observed diffusivity differences between young and adult muscles may be caused by increased membrane permeability in younger muscle associated with properties of the sarcolemma. Copyright © 2018 John Wiley & Sons, Ltd.

Dose of Phenobarbital and Age of Treatment at Early Life are Two Key Factors for the Persistent Induction of Cytochrome P450 Enzymes in Adult Mouse Liver

PubMed Central

Tien, Yun-Chen; Liu, Ke; Pope, Chad; Wang, Pengcheng; Ma, Xiaochao

2015-01-01

Drug treatment of neonates and infants and its long-term consequences on drug responses have emerged in recent years as a major challenge for health care professionals. In the current study, we use phenobarbital as a model drug and mouse as an in vivo model to demonstrate that the dose of phenobarbital and age of treatment are two key factors for the persistent induction of gene expression and consequential increases of enzyme activities of Cyp2b, Cyp2c, and Cyp3a in adult livers. We show that phenobarbital treatment at early life of day 5 after birth with a low dose (<100 mg/kg) does not change expression and enzyme activities of Cyp2b, Cyp2c, and Cyp3a in adult mouse liver, whereas phenobarbital treatment with a high dose (>200 mg/kg) significantly increases expression and enzyme activities of these P450s in adult liver. We also demonstrate that phenobarbital treatment before day 10 after birth, but not at later ages, significantly increases mRNAs, proteins, and enzyme activities of the tested P450s. Such persistent induction of P450 gene expression and enzyme activities in adult livers by phenobarbital treatment only occurs within a sensitive age window early in life. The persistent induction in gene expression and enzyme activities is higher in female mice than in male mice for Cyp2b10 but not for Cyp2c29 and Cyp3a11. These results will stimulate studies to evaluate the long-term impacts of drug treatment with different doses at neonatal and infant ages on drug metabolism, therapeutic efficacy, and drug-induced toxicity throughout the rest of life. PMID:26400395

Dose of Phenobarbital and Age of Treatment at Early Life are Two Key Factors for the Persistent Induction of Cytochrome P450 Enzymes in Adult Mouse Liver.

PubMed

Tien, Yun-Chen; Liu, Ke; Pope, Chad; Wang, Pengcheng; Ma, Xiaochao; Zhong, Xiao-bo

2015-12-01

Drug treatment of neonates and infants and its long-term consequences on drug responses have emerged in recent years as a major challenge for health care professionals. In the current study, we use phenobarbital as a model drug and mouse as an in vivo model to demonstrate that the dose of phenobarbital and age of treatment are two key factors for the persistent induction of gene expression and consequential increases of enzyme activities of Cyp2b, Cyp2c, and Cyp3a in adult livers. We show that phenobarbital treatment at early life of day 5 after birth with a low dose (<100 mg/kg) does not change expression and enzyme activities of Cyp2b, Cyp2c, and Cyp3a in adult mouse liver, whereas phenobarbital treatment with a high dose (>200 mg/kg) significantly increases expression and enzyme activities of these P450s in adult liver. We also demonstrate that phenobarbital treatment before day 10 after birth, but not at later ages, significantly increases mRNAs, proteins, and enzyme activities of the tested P450s. Such persistent induction of P450 gene expression and enzyme activities in adult livers by phenobarbital treatment only occurs within a sensitive age window early in life. The persistent induction in gene expression and enzyme activities is higher in female mice than in male mice for Cyp2b10 but not for Cyp2c29 and Cyp3a11. These results will stimulate studies to evaluate the long-term impacts of drug treatment with different doses at neonatal and infant ages on drug metabolism, therapeutic efficacy, and drug-induced toxicity throughout the rest of life. Copyright © 2015 by The American Society for Pharmacology and Experimental Therapeutics.

Haploinsufficiency for Translation Elongation Factor eEF1A2 in Aged Mouse Muscle and Neurons Is Compatible with Normal Function

PubMed Central

Griffiths, Lowri A.; Doig, Jennifer; Churchhouse, Antonia M. D.; Davies, Faith C. J.; Squires, Charlotte E.; Newbery, Helen J.; Abbott, Catherine M.

2012-01-01

Translation elongation factor isoform eEF1A2 is expressed in muscle and neurons. Deletion of eEF1A2 in mice gives rise to the neurodegenerative phenotype “wasted” (wst). Mice homozygous for the wasted mutation die of muscle wasting and neurodegeneration at four weeks post-natal. Although the mutation is said to be recessive, aged heterozygous mice have never been examined in detail; a number of other mouse models of motor neuron degeneration have recently been shown to have similar, albeit less severe, phenotypic abnormalities in the heterozygous state. We therefore examined the effects of ageing on a cohort of heterozygous +/wst mice and control mice, in order to establish whether a presumed 50% reduction in eEF1A2 expression was compatible with normal function. We evaluated the grip strength assay as a way of distinguishing between wasted and wild-type mice at 3–4 weeks, and then performed the same assay in older +/wst and wild-type mice. We also used rotarod performance and immunohistochemistry of spinal cord sections to evaluate the phenotype of aged heterozygous mice. Heterozygous mutant mice showed no deficit in neuromuscular function or signs of spinal cord pathology, in spite of the low levels of eEF1A2. PMID:22848658

Refractive index measurement of the mouse crystalline lens using optical coherence tomography.

PubMed

Chakraborty, Ranjay; Lacy, Kip D; Tan, Christopher C; Park, Han Na; Pardue, Machelle T

2014-08-01

In recent years, there has been a growing interest for using mouse models in refractive development and myopia research. The crystalline lens is a critical optical component of the mouse eye that occupies greater than 50% of the ocular space, and significant increases in thickness with age. However, changes in refractive index of the mouse crystalline lens are less known. In this study, we examined the changes in thickness and refractive index of the mouse crystalline lens for two different strains, wild-type (WT) and a nyx mutant (nob) over the course of normal visual development or after form deprivation. Refractive index and lens thickness measurements were made on ex vivo lenses using spectral domain optical coherence tomography (SD-OCT). Comparison of refractive index measurements on 5 standard ball lenses using the SD-OCT and their known refractive indices (manufacturer provided) indicated good precision (intra-class correlation coefficient, 0.998 and Bland-Altman coefficient of repeatability, 0.116) of the SD-OCT to calculate mouse lens refractive index ex vivo. During normal visual development, lens thickness increased significantly with age for three different cohorts of mice, aged 4 (average thickness from both eyes; WT: 1.78 ± 0.03, nob: 1.79 ± 0.08 mm), 10 (WT: 2.02 ± 0.05, nob: 2.01 ± 0.04 mm) and 16 weeks (WT: 2.12 ± 0.06, nob: 2.09 ± 0.06 mm, p < 0.001). Lens thickness was not significantly different between the two strains at any age (p = 0.557). For mice with normal vision, refractive index for isolated crystalline lenses in nob mice was significantly greater than WT mice (mean for all ages; WT: 1.42 ± 0.01, nob: 1.44 ± 0.001, p < 0.001). After 4 weeks of form deprivation to the right eye using a skull-mounted goggling apparatus, a thinning of the crystalline lens was observed in both right and left eyes of goggled animals compared to their naïve controls (average from both the right and the left eye) for both

Expression of G protein estrogen receptor (GPER) on membrane of mouse oocytes during maturation.

PubMed

Li, Yi-Ran; Ren, Chun-E; Zhang, Quan; Li, Ji-Chun; Chian, Ri-Cheng

2013-02-01

To determine expression of G-protein estrogen receptor (GPER) in mouse oocyte membrane during maturation. The expression of GPER from different maturation stages of oocytes, in vivo and in vitro matured oocytes as well as aging oocytes was examined by immune-fluorescence GPR30 antibody and the images were analyzed by laser scanning confocal microscope. Further confirmation was performed by Western blots for cell fractionation. Significant fluorescent signal was observed on the surface of mouse oocytes. The image expression was lower in germinal vesicle (GV) stage than mature metaphase-II (M-II) stage oocytes. There was high expression in in-vivo matured oocytes compared to in vitro matured oocytes. The highest expression was observed in aging oocytes compared with other oocytes. The changes of expression of GPER on mouse oocytes plasma membrane confirm oocyte membrane maturation, suggesting that those changes of GPER may be related to the functional role of oocyte maturation.

Lentivirus-mediated klotho up-regulation improves aging-related memory deficits and oxidative stress in senescence-accelerated mouse prone-8 mice.

PubMed

Zhou, Hong-Jing; Zeng, Chen-Ye; Yang, Ting-Ting; Long, Fang-Yi; Kuang, Xi; Du, Jun-Rong

2018-05-01

Oxidative stress caused by aging aggravates neuropathological changes and cognitive deficits. Klotho, an anti-aging protein, shows an anti-oxidative effect. The aims of the present study were to determine the potential therapeutic effect of klotho in aging-related neuropathological changes and memory impairments in senescence-accelerated mouse prone-8 (SAMP8) mice, and identify the potential mechanism of these neuroprotective effects. A lentivirus was used to deliver and sustain the expression of klotho. The lentiviral vectors were injected into the bilateral lateral ventricles of 7-month-old SAMP8 mice or age-matched SAMR1 mice. Three months later, the Y-maze alternation task and passive avoidance task were used to assess the memory deficits of the mice. In situ hybridization, immunohistochemistry, immunofluorescence, Nissl staining, quantitative real-time PCR and Western blot assays were applied in the following research. Our results showed that 3 months after injection of the lentiviral vectors encoding the full-length klotho gene, the expression of klotho in the brain was significantly increased in 10-month-old SAMP8 mice. This treatment reduced memory deficits, neuronal loss, synaptic damage and 4-HNE levels but increased mitochondrial manganese-superoxide dismutase (Mn-SOD) and catalase (CAT) expression. Moreover, the up-regulation of klotho expression decreased Akt and Forkhead box class O1 (FoxO1) phosphorylation. The present study provides a novel approach for klotho gene therapy and demonstrates that direct up-regulation of klotho in the brain might improve aging-related memory impairments and decrease oxidative stress. The underlying mechanism of this effect likely involves the inhibition of the Akt/FoxO1 pathway. Copyright © 2018 Elsevier Inc. All rights reserved.

CRISPR-LbCpf1 prevents choroidal neovascularization in a mouse model of age-related macular degeneration.

PubMed

Koo, Taeyoung; Park, Sung Wook; Jo, Dong Hyun; Kim, Daesik; Kim, Jin Hyoung; Cho, Hee-Yeon; Kim, Jeungeun; Kim, Jeong Hun; Kim, Jin-Soo

2018-05-10

LbCpf1, derived from Lachnospiraceae bacterium ND2006, is a CRISPR RNA-guided endonuclease and holds promise for therapeutic applications. Here we show that LbCpf1 can be used for therapeutic gene editing in a mouse model of age-related macular degeneration (AMD). The intravitreal delivery of LbCpf1, targeted to two angiogenesis-associated genes encoding vascular endothelial growth factor A (Vegfa) and hypoxia inducing factor 1a (Hif1a), using adeno-associated virus, led to efficient gene disruption with no apparent off-target effects in the retina and retinal pigment epithelium (RPE) cells. Importantly, LbCpf1 targeted to Vegfa or Hif1a in RPE cells reduced the area of laser-induced choroidal neovascularization as efficiently as aflibercept, an anti-VEGF drug currently used in the clinic, without inducing cone dysfunction. Unlike aflibercept, LbCpf1 targeted to Vegfa or Hif1a achieved a long-term therapeutic effect on CNV, potentially avoiding repetitive injections. Taken together, these results indicate that LbCpf1-mediated in vivo genome editing to ablate pathologic angiogenesis provides an effective strategy for the treatment of AMD and other neovascularization-associated diseases.

Mouse Sensitization and Exposure Are Associated with Asthma Severity in Urban Children.

PubMed

Grant, Torie; Aloe, Charles; Perzanowski, Matthew; Phipatanakul, Wanda; Bollinger, Mary E; Miller, Rachel; Matsui, Elizabeth C

Mouse sensitization and exposure are associated with uncontrolled asthma, but whether they are associated with asthma severity, an intrinsic disease characteristic and long-term outcome predictor, is unclear. To examine relationships between mouse sensitization and/or exposure and asthma severity in urban children. A total of 645 children (5-17 years) with uncontrolled asthma underwent mouse sensitization evaluation. Sensitized children had mouse allergen measured in bedroom dust. Relationships between mouse sensitization, allergen levels, and asthma severity measures (treatment step and Composite Asthma Severity Index [CASI]) were examined using regression models adjusted for age, sex, atopy, study site, race, ethnicity, and insurance. The study population was predominantly minority (69.6% black, 20.8% Hispanic), low income (61.8%), and mouse sensitized (54.4%). Mean ± SD treatment step was 3.2 ± 1.6, equivalent to medium-dose inhaled corticosteroid. Mean ± SD CASI was 6.5 ± 3.4, reflecting moderate persistent asthma. Mouse sensitization was associated with higher treatment step (3.5 vs 2.9, mouse-sensitized vs nonsensitized, P < .001), independent of potential confounders (β [95% CI], 0.36 [0.07-0.64]; P = .01). Mouse sensitization was associated independently with CASI (β [95% CI], 0.82 [0.16-1.47]; P = .02). Among mouse-sensitized participants, higher bedroom floor and bed Mus m 1 were independently associated with treatment step (β [95% CI], 0.26 [0.09-0.43]; P = .002 and β [95% CI], 0.22 [0.01-0.43]; P = .04), respectively. Higher bedroom floor Mus m 1 was independently associated with CASI (β [95% CI], 0.43 [0.05-0.81]; P = .03). Mouse sensitization and exposure are associated with asthma severity, among low-income, minority children. Further studies are needed to determine whether reducing allergen exposure among mouse-sensitized patients with asthma can reduce severity, ultimately altering childhood asthma natural history. Copyright �

Age-related cognitive impairment is associated with long-term neuroinflammation and oxidative stress in a mouse model of episodic systemic inflammation.

PubMed

d'Avila, Joana Costa; Siqueira, Luciana Domett; Mazeraud, Aurélien; Azevedo, Estefania Pereira; Foguel, Debora; Castro-Faria-Neto, Hugo Caire; Sharshar, Tarek; Chrétien, Fabrice; Bozza, Fernando Augusto

2018-01-30

Microglia function is essential to maintain the brain homeostasis. Evidence shows that aged microglia are primed and show exaggerated response to acute inflammatory challenge. Systemic inflammation signals to the brain inducing changes that impact cognitive function. However, the mechanisms involved in age-related cognitive decline associated to episodic systemic inflammation are not completely understood. The aim of this study was to identify neuropathological features associated to age-related cognitive decline in a mouse model of episodic systemic inflammation. Young and aged Swiss mice were injected with low doses of LPS once a week for 6 weeks to induce episodic systemic inflammation. Sickness behavior, inflammatory markers, and neuroinflammation were assessed in different phases of systemic inflammation in young and aged mice. Behavior was evaluated long term after episodic systemic inflammation by open field, forced swimming, object recognition, and water maze tests. Episodic systemic inflammation induced systemic inflammation and sickness behavior mainly in aged mice. Systemic inflammation induced depressive-like behavior in both young and aged mice. Memory and learning were significantly affected in aged mice that presented lower exploratory activity and deficits in episodic and spatial memories, compared to aged controls and to young after episodic systemic inflammation. Systemic inflammation induced acute microglia activation in young mice that returned to base levels long term after episodic systemic inflammation. Aged mice presented dystrophic microglia in the hippocampus and entorhinal cortex at basal level and did not change morphology in the acute response to SI. Regardless of their dystrophic microglia, aged mice produced higher levels of pro-inflammatory (IL-1β and IL-6) as well as pro-resolution (IL-10 and IL-4) cytokines in the brain. Also, higher levels of Nox2 expression, oxidized proteins and lower antioxidant defenses were found in the

Characterization of a novel genetically obese mouse model demonstrating early onset hyperphagia and hyperleptinemia.

PubMed

Nakahara, Keiko; Bannai, Makoto; Maruyama, Keisuke; Suzuki, Yoshihiro; Okame, Rieko; Murakami, Noboru

2013-08-01

Obesity is a critical risk factor for the development of metabolic syndrome, and many obese animal models are used to investigate the mechanisms responsible for the appearance of symptoms. To establish a new obese mouse model, we screened ∼13,000 ICR mice and discovered a mouse demonstrating spontaneous obesity. We named this mouse "Daruma" after a traditional Japanese ornament. Following the fixation of the genotype, these animals exhibited obese phenotypes according to Mendel's law of inheritance. In the Daruma mouse, the leptin receptor gene sequence carried two base mutations that are good candidates for the variation(s) responsible for the obese phenotype. The Daruma mice developed characteristic visceral fat accumulation at 4 wk of age, and the white adipose and liver tissues exhibited increases in cell size and lipid droplets, respectively. No histological abnormalities were observed in other tissues of the Daruma mice, even after the mice reached 25 wk of age. Moreover, the onset of impaired leptin signaling was early and manifested as hyperleptinemia and hyperinsulinemia. Pair feeding completely inhibited obesity, although these mice rapidly developed hyperphagia and obesity followed by hyperleptinemia when pair feeding ceased and free-access feeding was permitted. Therefore, the Daruma mice exhibited unique characteristics and may be a good model for studying human metabolic syndrome.

The BALB/c mouse: Effect of standard vivarium lighting on retinal pathology during aging.

PubMed

Bell, Brent A; Kaul, Charles; Bonilha, Vera L; Rayborn, Mary E; Shadrach, Karen; Hollyfield, Joe G

2015-06-01

intensity of illumination of the groups. Advanced age and top row illuminance conditions resulted in significant photoreceptor cell loss as judged by decreased thickness of the ONL. Photoreceptor loss was preceded by both retinal infoldings and the presence of autofluorescent inflammatory cells in the outer retina, suggesting that these changes are early indicators of light toxicity in the BALB/cJ mouse. Copyright © 2015 Elsevier Ltd. All rights reserved.

Rat astrocytes are more supportive for mouse OPC self-renewal than mouse astrocytes in culture.

PubMed

Cheng, Xuejun; Xie, Binghua; Qi, Jiajun; Zhao, Xiaofeng; Zhang, Zunyi; Qiu, Mengsheng; Yang, Junlin

2017-09-01

Mouse primary oligodendrocyte precursor cells (OPCs) are increasingly used to study the molecular mechanisms underlying the phenotype changes in oligodendrocyte differentiation and axonal myelination observed in transgenic or mutant mouse models. However, mouse OPCs are much more difficult to be isolated by the simple dissociation culture of brain tissues than their rat counterparts. To date, the mechanisms underlying the species difference in OPC preparation remain obscure. In this study, we showed that astrocytes from rats have a stronger effect than those from mouse in promoting OPC proliferation and survival in vitro. Mouse astrocytes displayed significantly weaker viability in culture and reduced potential in maintaining OPC self-renewal, as confirmed by culturing OPCs with conditioned media from rat or mouse astrocytes. These results explained the reason for why stratified cultures of OPCs and astrocytes are difficult to be achieved in mouse CNS tissues. Based on these findings, we adopted inactivated rat astrocytes as feeder cells to support the self-renewal of mouse cortical OPCs and preparation of high-purity mouse OPCs. © 2016 Wiley Periodicals, Inc. Develop Neurobiol 77: 907-916, 2017. © 2016 Wiley Periodicals, Inc.

Are tropical small mammals physiologically vulnerable to Arrhenius effects and climate change?

PubMed

Lovegrove, Barry G; Canale, Cindy; Levesque, Danielle; Fluch, Gerhard; Reháková-Petrů, Milada; Ruf, Thomas

2014-01-01

There is some urgency in the necessity to incorporate physiological data into mechanistic, trait-based, demographic climate change models. Physiological responses at the individual level provide the mechanistic link between environmental changes and individual performances and hence population dynamics. Here we consider the causal relationship between ambient temperature (Ta) and metabolic rate (MR), namely, the Arrhenius effect, which is directly affected by global warming through increases in average global air temperatures and the increase in the frequency and intensity of extreme climate events. We measured and collated data for several small, free-ranging tropical arboreal mammals and evaluated their vulnerability to Arrhenius effects and putative heat stress associated with climate change. Skin temperatures (Tskin) were obtained from free-ranging tarsiers (Tarsius syrichta) on Bohol Island, Philippines. Core body temperature (Tb) was obtained from the greater hedgehog tenrec (Setifer setosus) and the gray brown mouse lemur (Microcebus ravelobensis) from Ankarafantsika, Madagascar. Tskin for another mouse lemur, Microcebus griseorufus, was obtained from the literature. All four species showed evidence of hyperthermia during the daytime rest phase in the form of either Tskin or Tb that was higher than the normothermic Tb during the nighttime active phase. Potentially, tropical arboreal mammals with the lowest MRs and Tb, such as tarsiers, are the most vulnerable to sustained heat stress because their Tb is already close to Ta. Climate change may involve increases in MRs due to Arrhenius effects, especially during the rest phase or during torpor and hibernation. The most likely outcome of increased Arrhenius effects with climate change will be an increase in energy expenditure at the expense of other critical functions such as reproduction or growth and will thus affect fitness. However, we propose that these hypothetical Arrhenius costs can be, and in some

Building a Brainier Mouse.

ERIC Educational Resources Information Center

Tsien, Joe Z.

2000-01-01

Describes a genetic engineering project to build an intelligent mouse. Cites understanding the molecular basis of learning and memory as a very important step. Concludes that while science will never create a genius mouse that plays the stock market, it can turn a mouse into a quick learner with a better memory. (YDS)

Cord blood versus age 5 mononuclear cell proliferation on IgE and asthma

PubMed Central

2010-01-01

Background Fetal immune responses following exposure of mothers to allergens during pregnancy may influence the subsequent risk of childhood asthma. However, the association of allergen-induced cord blood mononuclear cell (CBMC) proliferation and cytokine production with later allergic immune responses and asthma has been controversial. Our objective was to compare indoor allergen-induced CBMC with age 5 peripheral blood mononuclear cell (PBMC) proliferation and determine which may be associated with age 5 allergic immune responses and asthma in an inner city cohort. Methods As part of an ongoing cohort study of the Columbia Center for Children's Environmental Health (CCCEH), CBMCs and age 5 PBMCs were cultured with cockroach, mouse, and dust mite protein extracts. CBMC proliferation and cytokine (IL-5 and IFN-γ) responses, and age 5 PBMC proliferation responses, were compared to anti-cockroach, anti-mouse, and anti-dust mite IgE levels, wheeze, cough, eczema and asthma. Results Correlations between CBMC and age 5 PBMC proliferation in response to cockroach, mouse, and dust mite antigens were nonsignificant. Cockroach-, mouse-, and dust mite-induced CBMC proliferation and cytokine responses were not associated with allergen-specific IgE at ages 2, 3, and 5, or with asthma and eczema at age 5. However, after adjusting for potential confounders, age 5 cockroach-induced PBMC proliferation was associated with anti-cockroach IgE, total IgE, and asthma (p < 0.05). Conclusion In contrast to allergen-induced CBMC proliferation, age 5 cockroach-induced PBMC proliferation was associated with age 5 specific and total IgE, and asthma, in an inner-city cohort where cockroach allergens are prevalent and exposure can be high. PMID:20684781

Imaging Redox State in Mouse Muscles of Different Ages.

PubMed

Moon, Lily; Frederick, David W; Baur, Joseph A; Li, Lin Z

2017-01-01

Aging is the greatest risk factor for many diseases. Intracellular concentrations of nicotinamide adenine dinucleotide (NAD + ) and the NAD + -coupled redox state have been proposed to moderate many aging-related processes, yet the specific mechanisms remain unclear. The concentration of NAD + falls with age in skeletal muscle, yet there is no consensus on whether aging will increase or decrease the redox potential of NAD + /NADH. Oxidized flavin groups (Fp) (e.g. FAD, i.e., flavin adenine dinucleotide, contained in flavoproteins) and NADH are intrinsic fluorescent indicators of oxidation and reduction status of tissue, respectively. The redox ratio, i.e., the ratio of Fp to NADH, may be a surrogate indicator of the NAD + /NADH redox potential. In this study we used the Chance redox scanner (NADH/Fp fluorescence imaging at low temperature) to investigate the effect of aging on the redox state of mitochondria in skeletal muscles. The results showed that there are borderline significant differences in nominal concentrations of Fp and NADH, but not in the redox ratio s when comparing 3.5-month and 13-month old muscles of mice (n = 6). It may be necessary to increase the number of muscle samples and study mice of more advanced age.

77 FR 34059 - Endangered Species; Receipt of Applications for Permit

Federal Register 2010, 2011, 2012, 2013, 2014

2012-06-08

... leopard (Uncia uncia) African wild dog (Lycaon pictus) Cheetah (Acinonyx jubatus) Applicant: M. Knudsen... radiata) salmon-crested cockatoo (Cacatua moluccensis) ring-tailed lemur (Lemur catta) black-and-white... (Spheniscus demersus) Andean condor (Vultur gryphus) White-naped crane (Grus vipio) Salmon-crested cockatoo...

Expression of Human Complement Factor H Prevents Age-Related Macular Degeneration–Like Retina Damage and Kidney Abnormalities in Aged Cfh Knockout Mice

PubMed Central

Ding, Jin-Dong; Kelly, Una; Landowski, Michael; Toomey, Christopher B.; Groelle, Marybeth; Miller, Chelsey; Smith, Stephanie G.; Klingeborn, Mikael; Singhapricha, Terry; Jiang, Haixiang; Frank, Michael M.; Bowes Rickman, Catherine

2016-01-01

Complement factor H (CFH) is an important regulatory protein in the alternative pathway of the complement system, and CFH polymorphisms increase the genetic risk of age-related macular degeneration dramatically. These same human CFH variants have also been associated with dense deposit disease. To mechanistically study the function of CFH in the pathogenesis of these diseases, we created transgenic mouse lines using human CFH bacterial artificial chromosomes expressing full-length human CFH variants and crossed these to Cfh knockout (Cfh−/−) mice. Human CFH protein inhibited cleavage of mouse complement component 3 and factor B in plasma and in retinal pigment epithelium/choroid/sclera, establishing that human CFH regulates activation of the mouse alternative pathway. One of the mouse lines, which express relatively higher levels of CFH, demonstrated functional and structural protection of the retina owing to the Cfh deletion. Impaired visual function, detected as a deficit in the scotopic electroretinographic response, was improved in this transgenic mouse line compared with Cfh−/− mice, and transgenics had a thicker outer nuclear layer and less sub–retinal pigment epithelium deposit accumulation. In addition, expression of human CFH also completely protected the mice from developing kidney abnormalities associated with loss of CFH. These humanized CFH mice present a valuable model for study of the molecular mechanisms of age-related macular degeneration and dense deposit disease and for testing therapeutic targets. PMID:25447048

Lack of Intrinsic GABAergic Connections in the Thalamic Reticular Nucleus of the Mouse.

PubMed

Hou, Guoqiang; Smith, Alison G; Zhang, Zhong-Wei

2016-07-06

It is generally thought that neurons in the thalamic reticular nucleus (TRN) form GABAergic synapses with other TRN neurons and that these interconnections are important for the function of the TRN. However, the existence of such intrinsic connections is controversial. We combine two complementary approaches to examine intrinsic GABAergic connections in the TRN of the mouse. We find that optogenetic stimulation of TRN neurons and their axons evokes GABAergic IPSCs in TRN neurons in mice younger than 2 weeks of age but fails to do so after that age. Blocking synaptic release from TRN neurons through conditional deletion of vesicular GABA transporter has no effect on spontaneous IPSCs recorded in TRN neurons aged 2 weeks or older while dramatically reducing GABAergic transmission in thalamic relay neurons. These results demonstrate that except for a short period after birth, the TRN of the mouse lacks intrinsic GABAergic connections. The thalamic reticular nucleus has a critical role in modulating information transfer from the thalamus to the cortex. It has been proposed that neurons in the thalamic reticular nucleus are interconnected through GABAergic synapses and that these connections serve important functions. Our results show that except for the first 2 weeks after birth, the thalamic reticular nucleus of the mouse lacks intrinsic GABAergic connections. Copyright © 2016 the authors 0270-6474/16/367246-07$15.00/0.

Whole mouse cryo-imaging

NASA Astrophysics Data System (ADS)

Wilson, David; Roy, Debashish; Steyer, Grant; Gargesha, Madhusudhana; Stone, Meredith; McKinley, Eliot

2008-03-01

The Case cryo-imaging system is a section and image system which allows one to acquire micron-scale, information rich, whole mouse color bright field and molecular fluorescence images of an entire mouse. Cryo-imaging is used in a variety of applications, including mouse and embryo anatomical phenotyping, drug delivery, imaging agents, metastastic cancer, stem cells, and very high resolution vascular imaging, among many. Cryo-imaging fills the gap between whole animal in vivo imaging and histology, allowing one to image a mouse along the continuum from the mouse -> organ -> tissue structure -> cell -> sub-cellular domains. In this overview, we describe the technology and a variety of exciting applications. Enhancements to the system now enable tiled acquisition of high resolution images to cover an entire mouse. High resolution fluorescence imaging, aided by a novel subtraction processing algorithm to remove sub-surface fluorescence, makes it possible to detect fluorescently-labeled single cells. Multi-modality experiments in Magnetic Resonance Imaging and Cryo-imaging of a whole mouse demonstrate superior resolution of cryo-images and efficiency of registration techniques. The 3D results demonstrate the novel true-color volume visualization tools we have developed and the inherent advantage of cryo-imaging in providing unlimited depth of field and spatial resolution. The recent results continue to demonstrate the value cryo-imaging provides in the field of small animal imaging research.

The Mouse Genome Database (MGD): facilitating mouse as a model for human biology and disease.

PubMed

Eppig, Janan T; Blake, Judith A; Bult, Carol J; Kadin, James A; Richardson, Joel E

2015-01-01

The Mouse Genome Database (MGD, http://www.informatics.jax.org) serves the international biomedical research community as the central resource for integrated genomic, genetic and biological data on the laboratory mouse. To facilitate use of mouse as a model in translational studies, MGD maintains a core of high-quality curated data and integrates experimentally and computationally generated data sets. MGD maintains a unified catalog of genes and genome features, including functional RNAs, QTL and phenotypic loci. MGD curates and provides functional and phenotype annotations for mouse genes using the Gene Ontology and Mammalian Phenotype Ontology. MGD integrates phenotype data and associates mouse genotypes to human diseases, providing critical mouse-human relationships and access to repositories holding mouse models. MGD is the authoritative source of nomenclature for genes, genome features, alleles and strains following guidelines of the International Committee on Standardized Genetic Nomenclature for Mice. A new addition to MGD, the Human-Mouse: Disease Connection, allows users to explore gene-phenotype-disease relationships between human and mouse. MGD has also updated search paradigms for phenotypic allele attributes, incorporated incidental mutation data, added a module for display and exploration of genes and microRNA interactions and adopted the JBrowse genome browser. MGD resources are freely available to the scientific community. © The Author(s) 2014. Published by Oxford University Press on behalf of Nucleic Acids Research.

High-Frequency Ultrasound for the Study of Early Mouse Embryonic Cardiovascular System.

PubMed

Greco, Adelaide; Coda, Anna Rita Daniela; Albanese, Sandra; Ragucci, Monica; Liuzzi, Raffaele; Auletta, Luigi; Gargiulo, Sara; Lamagna, Francesco; Salvatore, Marco; Mancini, Marcello

2015-12-01

An accurate diagnosis of congenital heart defects during fetal development is critical for interventional planning. Mice can be used to generate animal models with heart defects, and high-frequency ultrasound (HFUS) imaging enables in utero imaging of live mouse embryos. A wide range of physiological measurements is possible using Doppler-HFUS imaging; limitations of any single measurement warrant a multiparameter approach to characterize cardiovascular function. Doppler-HFUS was used to explore the embryonic (heart, aorta) and extraembryonic (umbilical blood flow) circulatory systems to create a database in normal mouse embryos between 9.5 and 16.5 days of gestation. Multivariate analyses were performed to explore correlations between gestational age and embryo echocardiographic parameters. Heart rate and peak velocity in the aorta were positively correlated with gestational time, whereas cardiac cycle length, isovolumetric relaxation time, myocardial performance index, and arterial deceleration time of the umbilical cord were negatively correlated with it. Doppler-HFUS facilitated detailed characterization of the embryonic mouse circulation and represents a useful tool for investigation of the early mouse embryonic cardiovascular system. © The Author(s) 2015.

Hypothalamic stem cells control ageing speed partly through exosomal miRNAs.

PubMed

Zhang, Yalin; Kim, Min Soo; Jia, Baosen; Yan, Jingqi; Zuniga-Hertz, Juan Pablo; Han, Cheng; Cai, Dongsheng

2017-08-03

It has been proposed that the hypothalamus helps to control ageing, but the mechanisms responsible remain unclear. Here we develop several mouse models in which hypothalamic stem/progenitor cells that co-express Sox2 and Bmi1 are ablated, as we observed that ageing in mice started with a substantial loss of these hypothalamic cells. Each mouse model consistently displayed acceleration of ageing-like physiological changes or a shortened lifespan. Conversely, ageing retardation and lifespan extension were achieved in mid-aged mice that were locally implanted with healthy hypothalamic stem/progenitor cells that had been genetically engineered to survive in the ageing-related hypothalamic inflammatory microenvironment. Mechanistically, hypothalamic stem/progenitor cells contributed greatly to exosomal microRNAs (miRNAs) in the cerebrospinal fluid, and these exosomal miRNAs declined during ageing, whereas central treatment with healthy hypothalamic stem/progenitor cell-secreted exosomes led to the slowing of ageing. In conclusion, ageing speed is substantially controlled by hypothalamic stem cells, partially through the release of exosomal miRNAs.

NCI Mouse Repository | FNLCR Staging

Cancer.gov

The NCI Mouse Repository is an NCI-funded resource for mouse cancer models and associated strains. The repository makes strains available to all members of the scientific community (academic, non-profit, and commercial). NCI Mouse Repository strains

Archiving and Distributing Mouse Lines by Sperm Cryopreservation, IVF, and Embryo Transfer

PubMed Central

Takahashi, Hideko; Liu, Chengyu

2012-01-01

The number of genetically modified mouse lines has been increasing exponentially in the past few decades. In order to safeguard them from accidental loss and genetic drifting, to reduce animal housing cost, and to efficiently distribute them around the world, it is important to cryopreserve these valuable genetic resources. Preimplantation-stage embryos from thousands of mouse lines have been cryopreserved during the past two to three decades. Although reliable, this method requires several hundreds of embryos, which demands a sizable breeding colony, to safely preserve each line. This requirement imposes significant delay and financial burden for the archiving effort. Sperm cryopreservation is now emerging as the leading method for storing and distributing mouse lines, largely due to the recent finding that addition of a reducing agent, monothioglycerol, into the cryoprotectant can significantly increase the in vitro fertilization (IVF) rate in many mouse strains, including the most widely used C57BL/6 strain. This method is quick, inexpensive, and requires only two breeding age male mice, but it still remains tricky and strain-dependent. A small change in experimental conditions can lead to significant variations in the outcome. In this chapter, we describe in detail our sperm cryopreservation, IVF, and oviduct transfer procedures for storing and reviving genetically modified mouse lines. PMID:20691860

The Mouse Genomes Project: a repository of inbred laboratory mouse strain genomes.

PubMed

Adams, David J; Doran, Anthony G; Lilue, Jingtao; Keane, Thomas M

2015-10-01

The Mouse Genomes Project was initiated in 2009 with the goal of using next-generation sequencing technologies to catalogue molecular variation in the common laboratory mouse strains, and a selected set of wild-derived inbred strains. The initial sequencing and survey of sequence variation in 17 inbred strains was completed in 2011 and included comprehensive catalogue of single nucleotide polymorphisms, short insertion/deletions, larger structural variants including their fine scale architecture and landscape of transposable element variation, and genomic sites subject to post-transcriptional alteration of RNA. From this beginning, the resource has expanded significantly to include 36 fully sequenced inbred laboratory mouse strains, a refined and updated data processing pipeline, and new variation querying and data visualisation tools which are available on the project's website ( http://www.sanger.ac.uk/resources/mouse/genomes/ ). The focus of the project is now the completion of de novo assembled chromosome sequences and strain-specific gene structures for the core strains. We discuss how the assembled chromosomes will power comparative analysis, data access tools and future directions of mouse genetics.

Transplantation of Adipose Derived Stromal Cells into the Developing Mouse Eye

PubMed Central

Yu, Song-Hee; Jang, Yu-Jin; Lee, Eun-Shil; Hwang, Dong-Youn; Jeon, Chang-Jin

2010-01-01

Adipose derived stromal cells (ADSCs) were transplanted into a developing mouse eye to investigate the influence of a developing host micro environment on integration and differentiation. Green fluorescent protein-expressing ADSCs were transplanted by intraocular injections. The age of the mouse was in the range of 1 to 10 days postnatal (PN). Survival dates ranged from 7 to 28 post transplantation (DPT), at which time immunohistochemistry was performed. The transplanted ADSCs displayed some morphological differentiations in the host eye. Some cells expressed microtubule associated protein 2 (marker for mature neuron), or glial fibrillary acid protein (marker for glial cell). In addition, some cells integrated into the ganglion cell layer. The integration and differentiation of the transplanted ADSCs in the 5 and 10 PN 7 DPT were better than in the host eye the other age ranges. This study was aimed at demonstrating how the age of host micro environment would influence the differentiation and integration of the transplanted ADSCs. However, it was found that the integration and differentiation into the developing retina were very limited when compared with other stem cells, such as murine brain progenitor cell. PMID:21245978

Cell-autonomous progeroid changes in conditional mouse models for repair endonuclease XPG deficiency

DOE PAGES

Barnhoorn, Sander; Uittenboogaard, Lieneke M.; Jaarsma, Dick; ...

2014-10-09

As part of the Nucleotide Excision Repair (NER) process, the endonuclease XPG is involved in repair of helix-distorting DNA lesions, but the protein has also been implicated in several other DNA repair systems, complicating genotype-phenotype relationship in XPG patients. Defects in XPG can cause either the cancer-prone condition xeroderma pigmentosum (XP) alone, or XP combined with the severe neurodevelopmental disorder Cockayne Syndrome (CS), or the infantile lethal cerebro-oculo-facio-skeletal (COFS) syndrome, characterized by dramatic growth failure, progressive neurodevelopmental abnormalities and greatly reduced life expectancy. Here, we present a novel (conditional) Xpg -/- mouse model which—in a C57BL6/FVB F1 hybrid genetic background—displaysmore » many progeroid features, including cessation of growth, loss of subcutaneous fat, kyphosis, osteoporosis, retinal photoreceptor loss, liver aging, extensive neurodegeneration, and a short lifespan of 4–5 months. We show that deletion of XPG specifically in the liver reproduces the progeroid features in the liver, yet abolishes the effect on growth or lifespan. In addition, specific XPG deletion in neurons and glia of the forebrain creates a progressive neurodegenerative phenotype that shows many characteristics of human XPG deficiency. Our findings therefore exclude that both the liver as well as the neurological phenotype are a secondary consequence of derailment in other cell types, organs or tissues (e.g. vascular abnormalities) and support a cell-autonomous origin caused by the DNA repair defect itself. In addition they allow the dissection of the complex aging process in tissue- and cell-type-specific components. Moreover, our data highlight the critical importance of genetic background in mouse aging studies, establish the Xpg -/- mouse as a valid model for the severe form of human XPG patients and segmental accelerated aging, and strengthen the link between DNA damage and aging.« less

Cell-autonomous progeroid changes in conditional mouse models for repair endonuclease XPG deficiency

DOE Office of Scientific and Technical Information (OSTI.GOV)

Barnhoorn, Sander; Uittenboogaard, Lieneke M.; Jaarsma, Dick

As part of the Nucleotide Excision Repair (NER) process, the endonuclease XPG is involved in repair of helix-distorting DNA lesions, but the protein has also been implicated in several other DNA repair systems, complicating genotype-phenotype relationship in XPG patients. Defects in XPG can cause either the cancer-prone condition xeroderma pigmentosum (XP) alone, or XP combined with the severe neurodevelopmental disorder Cockayne Syndrome (CS), or the infantile lethal cerebro-oculo-facio-skeletal (COFS) syndrome, characterized by dramatic growth failure, progressive neurodevelopmental abnormalities and greatly reduced life expectancy. Here, we present a novel (conditional) Xpg -/- mouse model which—in a C57BL6/FVB F1 hybrid genetic background—displaysmore » many progeroid features, including cessation of growth, loss of subcutaneous fat, kyphosis, osteoporosis, retinal photoreceptor loss, liver aging, extensive neurodegeneration, and a short lifespan of 4–5 months. We show that deletion of XPG specifically in the liver reproduces the progeroid features in the liver, yet abolishes the effect on growth or lifespan. In addition, specific XPG deletion in neurons and glia of the forebrain creates a progressive neurodegenerative phenotype that shows many characteristics of human XPG deficiency. Our findings therefore exclude that both the liver as well as the neurological phenotype are a secondary consequence of derailment in other cell types, organs or tissues (e.g. vascular abnormalities) and support a cell-autonomous origin caused by the DNA repair defect itself. In addition they allow the dissection of the complex aging process in tissue- and cell-type-specific components. Moreover, our data highlight the critical importance of genetic background in mouse aging studies, establish the Xpg -/- mouse as a valid model for the severe form of human XPG patients and segmental accelerated aging, and strengthen the link between DNA damage and aging.« less

Comprehensive behavioral and molecular characterization of a new knock-in mouse model of Huntington's disease: zQ175.

PubMed

Menalled, Liliana B; Kudwa, Andrea E; Miller, Sam; Fitzpatrick, Jon; Watson-Johnson, Judy; Keating, Nicole; Ruiz, Melinda; Mushlin, Richard; Alosio, William; McConnell, Kristi; Connor, David; Murphy, Carol; Oakeshott, Steve; Kwan, Mei; Beltran, Jose; Ghavami, Afshin; Brunner, Dani; Park, Larry C; Ramboz, Sylvie; Howland, David

2012-01-01

Huntington's disease (HD) is an autosomal dominant neurodegenerative disorder characterized by motor, cognitive and psychiatric manifestations. Since the mutation responsible for the disease was identified as an unstable expansion of CAG repeats in the gene encoding the huntingtin protein in 1993, numerous mouse models of HD have been generated to study disease pathogenesis and evaluate potential therapeutic approaches. Of these, knock-in models best mimic the human condition from a genetic perspective since they express the mutation in the appropriate genetic and protein context. Behaviorally, however, while some abnormal phenotypes have been detected in knock-in mouse models, a model with an earlier and more robust phenotype than the existing models is required. We describe here for the first time a new mouse line, the zQ175 knock-in mouse, derived from a spontaneous expansion of the CAG copy number in our CAG 140 knock-in colony [1]. Given the inverse relationship typically observed between age of HD onset and length of CAG repeat, since this new mouse line carries a significantly higher CAG repeat length it was expected to be more significantly impaired than the parent line. Using a battery of behavioral tests we evaluated both heterozygous and homozygous zQ175 mice. Homozygous mice showed motor and grip strength abnormalities with an early onset (8 and 4 weeks of age, respectively), which were followed by deficits in rotarod and climbing activity at 30 weeks of age and by cognitive deficits at around 1 year of age. Of particular interest for translational work, we also found clear behavioral deficits in heterozygous mice from around 4.5 months of age, especially in the dark phase of the diurnal cycle. Decreased body weight was observed in both heterozygotes and homozygotes, along with significantly reduced survival in the homozygotes. In addition, we detected an early and significant decrease of striatal gene markers from 12 weeks of age. These data suggest

50 CFR 14.151 - Primary enclosures.

Code of Federal Regulations, 2010 CFR

2010-10-01

... Wildlife and Fisheries UNITED STATES FISH AND WILDLIFE SERVICE, DEPARTMENT OF THE INTERIOR TAKING... Wild Mammals and Birds to the United States Specifications for Sloths, Bats, and Flying Lemurs... located on the upper one-half of the primary enclosure. (b) No more than one sloth, bat, or flying lemur...

Cognitive Impairment, Neuroimaging, and Alzheimer Neuropathology in Mouse Models of Down Syndrome

PubMed Central

Hamlett, Eric D.; Boger, Heather A.; Ledreux, Aurélie; Kelley, Christy M.; Mufson, Elliott J.; Falangola, Maria F.; Guilfoyle, David N.; Nixon, Ralph A.; Patterson, David; Duval, Nathan; Granholm, Ann-Charlotte E.

2016-01-01

Down syndrome (DS) is the most common non-lethal genetic condition that affects approximately 1 in 700 births in the United States of America. DS is characterized by complete or segmental chromosome 21 trisomy, which leads to variable intellectual disabilities, progressive memory loss, and accelerated neurodegeneration with age. During the last three decades, people with DS have experienced a doubling of life expectancy due to progress in treatment of medical comorbidities, which has allowed this population to reach the age when they develop early onset Alzheimer’s disease (AD). Individuals with DS develop cognitive and pathological hallmarks of AD in their fourth or fifth decade, and are currently lacking successful prevention or treatment options for dementia. The profound memory deficits associated with DS-related AD (DS-AD) have been associated with degeneration of several neuronal populations, but mechanisms of neurodegeneration are largely unexplored. The most successful animal model for DS is the Ts65Dn mouse, but several new models have also been developed. In the current review, we discuss recent findings and potential treatment options for the management of memory loss and AD neuropathology in DS mouse models. We also review age-related neuropathology, and recent findings from neuroimaging studies. The validation of appropriate DS mouse models that mimic neurodegeneration and memory loss in humans with DS can be valuable in the study of novel preventative and treatment interventions, and may be helpful in pinpointing gene-gene interactions as well as specific gene segments involved in neurodegeneration. PMID:26391050

Sex effects in mouse prion disease incubation time.

PubMed

Akhtar, Shaheen; Wenborn, Adam; Brandner, Sebastian; Collinge, John; Lloyd, Sarah E

2011-01-01

Prion disease incubation time in mice is determined by many factors including PrP expression level, Prnp alleles, genetic background, prion strain and route of inoculation. Sex differences have been described in age of onset for vCJD and in disease duration for both vCJD and sporadic CJD and have also been shown in experimental models. The sex effects reported for mouse incubation times are often contradictory and detail only one strain of mice or prions, resulting in broad generalisations and a confusing picture. To clarify the effect of sex on prion disease incubation time in mice we have compared male and female transmission data from twelve different inbred lines of mice inoculated with at least two prion strains, representing both mouse-adapted scrapie and BSE. Our data show that sex can have a highly significant difference on incubation time. However, this is limited to particular mouse and prion strain combinations. No sex differences were seen in endogenous PrP(C) levels nor in the neuropathological markers of prion disease: PrP(Sc) distribution, spongiosis, neuronal loss and gliosis. These data suggest that when comparing incubation times between experimental groups, such as testing the effects of modifier genes or therapeutics, single sex groups should be used.

Mouse Tumor Biology (MTB): a database of mouse models for human cancer.

PubMed

Bult, Carol J; Krupke, Debra M; Begley, Dale A; Richardson, Joel E; Neuhauser, Steven B; Sundberg, John P; Eppig, Janan T

2015-01-01

The Mouse Tumor Biology (MTB; http://tumor.informatics.jax.org) database is a unique online compendium of mouse models for human cancer. MTB provides online access to expertly curated information on diverse mouse models for human cancer and interfaces for searching and visualizing data associated with these models. The information in MTB is designed to facilitate the selection of strains for cancer research and is a platform for mining data on tumor development and patterns of metastases. MTB curators acquire data through manual curation of peer-reviewed scientific literature and from direct submissions by researchers. Data in MTB are also obtained from other bioinformatics resources including PathBase, the Gene Expression Omnibus and ArrayExpress. Recent enhancements to MTB improve the association between mouse models and human genes commonly mutated in a variety of cancers as identified in large-scale cancer genomics studies, provide new interfaces for exploring regions of the mouse genome associated with cancer phenotypes and incorporate data and information related to Patient-Derived Xenograft models of human cancers. © The Author(s) 2014. Published by Oxford University Press on behalf of Nucleic Acids Research.

Finding mouse models of human lymphomas and leukemia's using the Jackson laboratory mouse tumor biology database.

PubMed

Begley, Dale A; Sundberg, John P; Krupke, Debra M; Neuhauser, Steven B; Bult, Carol J; Eppig, Janan T; Morse, Herbert C; Ward, Jerrold M

2015-12-01

Many mouse models have been created to study hematopoietic cancer types. There are over thirty hematopoietic tumor types and subtypes, both human and mouse, with various origins, characteristics and clinical prognoses. Determining the specific type of hematopoietic lesion produced in a mouse model and identifying mouse models that correspond to the human subtypes of these lesions has been a continuing challenge for the scientific community. The Mouse Tumor Biology Database (MTB; http://tumor.informatics.jax.org) is designed to facilitate use of mouse models of human cancer by providing detailed histopathologic and molecular information on lymphoma subtypes, including expertly annotated, on line, whole slide scans, and providing a repository for storing information on and querying these data for specific lymphoma models. Copyright © 2015 Elsevier Inc. All rights reserved.

Therapeutic cloning in the mouse

PubMed Central

Mombaerts, Peter

2003-01-01

Nuclear transfer technology can be applied to produce autologous differentiated cells for therapeutic purposes, a concept termed therapeutic cloning. Countless articles have been published on the ethics and politics of human therapeutic cloning, reflecting the high expectations from this new opportunity for rejuvenation of the aging or diseased body. Yet the research literature on therapeutic cloning, strictly speaking, is comprised of only four articles, all in the mouse. The efficiency of derivation of embryonic stem cell lines via nuclear transfer is remarkably consistent among these reports. However, the efficiency is so low that, in its present form, the concept is unlikely to become widespread in clinical practice. PMID:12949262

A Longitudinal Motor Characterisation of the HdhQ111 Mouse Model of Huntington's Disease.

PubMed

Yhnell, Emma; Dunnett, Stephen B; Brooks, Simon P

2016-05-31

Huntington's disease (HD) is a rare, incurable neurodegenerative disorder caused by a CAG trinucleotide expansion with the first exon of the huntingtin gene. Numerous knock-in mouse models are currently available for modelling HD. However, before their use in scientific research, these models must be characterised to determine their face and predictive validity as models of the disease and their reliability in recapitulating HD symptoms. Manifest HD is currently diagnosed upon the onset of motor symptoms, thus we sought to longitudinally characterise the progression and severity of motor signs in the HdhQ111 knock-in mouse model of HD, in heterozygous mice. An extensive battery of motor tests including: rotarod, inverted lid test, balance beam, spontaneous locomotor activity and gait analysis were applied longitudinally to a cohort of HdhQ111 heterozygous mice in order to progressively assess motor function. A progressive failure to gain body weight was demonstrated from 11 months of age and motor problems in all measures of balance beam performance were shown in HdhQ111 heterozygous animals in comparison to wild type control animals from 9 months of age. A decreased latency to fall from the rotarod was demonstrated in HdhQ111 heterozygous animals in comparison to wild type animals, although this was not progressive with time. No genotype specific differences were demonstrated in any of the other motor tests included in the test battery. The HdhQ111 heterozygous mouse demonstrates a subtle and progressive motor phenotype that begins at 9 months of age. This mouse model represents an early disease stage and would be ideal for testing therapeutic strategies that require elongated lead-in times, such as viral gene therapies or striatal transplantation.

Reward components of feeding behavior are preserved during mouse aging

PubMed Central

Harb, Mazen R.; Sousa, Nuno; Zihl, Joseph; Almeida, Osborne F. X.

2014-01-01

Eating behavior depends on associations between the sensory and energetic properties of foods. Healthful balance of these factors is a challenge for industrialized societies that have an abundance of food, food choices and food-related cues. Here, we were interested in whether appetitive conditioning changes as a function of age. Operant and pavlovian conditioning experiments (rewarding stimulus was a palatable food) in male mice (aged 3, 6, and 15 months) showed that implicit (non-declarative) memory remains intact during aging. Two other essential components of eating behavior, motivation and hedonic preference for rewarding foods, were also found not to be altered in aging mice. Specifically, hedonic responding by satiated mice to isocaloric foods of differing sensory properties (sucrose, milk) was similar in all age groups; importantly, however, this paradigm disclosed that older animals adjust their energy intake according to energetic need. Based on the assumption that the mechanisms that control feeding are conserved across species, it would appear that overeating and obesity in humans reflects a mismatch between ancient physiological mechanisms and today's cue-laden environment. The implication of the present results showing that aging does not impair the ability to learn stimulus-food associations is that the risk of overeating in response to food cues is maintained through to old age. PMID:25278876

Reward components of feeding behavior are preserved during mouse aging.

PubMed

Harb, Mazen R; Sousa, Nuno; Zihl, Joseph; Almeida, Osborne F X

2014-01-01

Eating behavior depends on associations between the sensory and energetic properties of foods. Healthful balance of these factors is a challenge for industrialized societies that have an abundance of food, food choices and food-related cues. Here, we were interested in whether appetitive conditioning changes as a function of age. Operant and pavlovian conditioning experiments (rewarding stimulus was a palatable food) in male mice (aged 3, 6, and 15 months) showed that implicit (non-declarative) memory remains intact during aging. Two other essential components of eating behavior, motivation and hedonic preference for rewarding foods, were also found not to be altered in aging mice. Specifically, hedonic responding by satiated mice to isocaloric foods of differing sensory properties (sucrose, milk) was similar in all age groups; importantly, however, this paradigm disclosed that older animals adjust their energy intake according to energetic need. Based on the assumption that the mechanisms that control feeding are conserved across species, it would appear that overeating and obesity in humans reflects a mismatch between ancient physiological mechanisms and today's cue-laden environment. The implication of the present results showing that aging does not impair the ability to learn stimulus-food associations is that the risk of overeating in response to food cues is maintained through to old age.

The MOUSE Squad

ERIC Educational Resources Information Center

Borja, Rhea R.

2004-01-01

This article presents a New York city after-school program started by MOUSE (Making Opportunities for Upgrading Schools and Education), a national nonprofit group that teaches students how to fix computers, and equips them with the communication and problem-solving skills to help them in the working world. The MOUSE program is part of a trend…

Age-Dependent Modulation of Synaptic Plasticity and Insulin Mimetic Effect of Lipoic Acid on a Mouse Model of Alzheimer’s Disease

PubMed Central

Sancheti, Harsh; Akopian, Garnik; Yin, Fei; Brinton, Roberta D.; Walsh, John P.; Cadenas, Enrique

2013-01-01

Alzheimer’s disease is a progressive neurodegenerative disease that entails impairments of memory, thinking and behavior and culminates into brain atrophy. Impaired glucose uptake (accumulating into energy deficits) and synaptic plasticity have been shown to be affected in the early stages of Alzheimer’s disease. This study examines the ability of lipoic acid to increase brain glucose uptake and lead to improvements in synaptic plasticity on a triple transgenic mouse model of Alzheimer’s disease (3xTg-AD) that shows progression of pathology as a function of age; two age groups: 6 months (young) and 12 months (old) were used in this study. 3xTg-AD mice fed 0.23% w/v lipoic acid in drinking water for 4 weeks showed an insulin mimetic effect that consisted of increased brain glucose uptake, activation of the insulin receptor substrate and of the PI3K/Akt signaling pathway. Lipoic acid supplementation led to important changes in synaptic function as shown by increased input/output (I/O) and long term potentiation (LTP) (measured by electrophysiology). Lipoic acid was more effective in stimulating an insulin-like effect and reversing the impaired synaptic plasticity in the old mice, wherein the impairment of insulin signaling and synaptic plasticity was more pronounced than those in young mice. PMID:23875003

Senescent Cells: A Novel Therapeutic Target for Aging and Age-Related Diseases

PubMed Central

Naylor, RM; Baker, DJ; van Deursen, JM

2014-01-01

Aging is the main risk factor for most chronic diseases, disabilities, and declining health. It has been proposed that senescent cells—damaged cells that have lost the ability to divide—drive the deterioration that underlies aging and age-related diseases. However, definitive evidence for this relationship has been lacking. The use of a progeroid mouse model (which expresses low amounts of the mitotic checkpoint protein BubR1) has been instrumental in demonstrating that p16Ink4a-positive senescent cells drive age-related pathologies and that selective elimination of these cells can prevent or delay age-related deterioration. These studies identify senescent cells as potential therapeutic targets in the treatment of aging and age-related diseases. Here, we describe how senescent cells develop, the experimental evidence that causally implicates senescent cells in age-related dysfunction, the chronic diseases and disorders that are characterized by the accumulation of senescent cells at sites of pathology, and the therapeutic approaches that could specifically target senescent cells. PMID:23212104

Age dependent regulation of bone-mass and renal function by the MEPE ASARM-motif

PubMed Central

Zelenchuk, Lesya V; Hedge, Anne-Marie; Rowe, Peter S N

2015-01-01

Context Mice with null mutations in Matrix Extracellular Phosphoglycoprotein (MEPE) have increased bone mass, increased trabecular density and abnormal cancellous bone (MN-mice). These defects worsen with age and MEPE over expression induces opposite effects. Also, Genome Wide Association studies show MEPE plays a major role in bone mass. We hypothesized the conserved C-terminal MEPE ASARM-motif is chiefly responsible for regulating bone mass and trabecular structure. Design To test our theory we over expressed C-terminal ASARM-peptide in MN-mice using the Col1α1 promoter (MNAt-mice). We then compared the bone and renal phenotypes of the MNAt-mouse with the MN-mouse and the X-linked hypophosphatemic rickets mouse (HYP). The HYP mouse over expresses ASARM-peptides and is defective for the PHEX gene. Results The MN-mouse developed increased bone mass, bone strength and trabecular abnormalities that worsened markedly with age. Defects in bone formation were chiefly responsible with suppressed sclerostin and increased active β-catenin. Increased uric acid levels also suggested abnormalities in purine-metabolism and a reduced fractional excretion of uric acid signaled additional renal transport changes. The MN mouse developed a worsening hyperphosphatemia and reduced FGF23 with age. An increase in the fractional excretion of phosphate (FEP) despite the hyperphosphatemia confirms an imbalance in kidney-intestinal phosphate regulation. Also, the MN mice showed an increased creatinine clearance suggesting hyperfiltration. A reversal of the MN bone-renal phenotype changes occurred with the MNAt mice including the apparent hyperfiltration. The MNAt mice also developed localized hypomineralization, hypophosphatemia and increased FGF23. Conclusions The C-terminal ASARM-motif plays a major role in regulating bone–mass and cancellous structure as mice age. In healthy mice, the processing and release of free ASARM-peptide is chiefly responsible for preserving normal bone and

Skin test sensitivity to mouse predicts allergic symptoms to nasal challenge in urban adults.

PubMed

Chong, Laura K; Ong, Mary Jane; Curtin-Brosnan, Jean; Matsui, Elizabeth C

2010-01-01

Epidemiologic studies have shown an association between mouse allergen exposure and asthma morbidity among urban populations, but confirmatory challenge studies in community populations have not been performed. This study was designed to examine the clinical relevance of mouse sensitization using a nasal challenge model. Forty-nine urban adults with asthma underwent skin-prick testing (SPT) and intradermal testing (IDT) with mouse epithelia extract. A positive SPT was defined as a net wheal size ≥3 mm and a positive IDT was defined as a net wheal size ≥6 mm using a 1:100 dilution of extract (1:10 w/v was obtained from Greer Laboratories (Lenoir, NC) as a single lot [Mus m 1 concentration = 2130 ng/mL]). Mouse-specific IgE (m-IgE) was measured by ImmunoCAP (Phadia, Uppsala, Sweden). Nasal challenge was performed with increasing concentrations of mouse epithelia extract and symptoms were assessed by visual analog scale. A positive challenge was defined as a 20-mm increase in the scale. The age range of the 49 participants was 18-50 years; 41% were men and 86% were black. Fourteen participants were SPT(+) to mouse, 15 participants were SPT(-) but (IDT(+)), and 20 participants were negative on both SPT(-) and IDT(-) (SPT(-)/IDT(-)). Sixty-four percent of the SPT(+) group, 40% of the IDT(+) group, and 20% of the SPT(-)/IDT(-) group had a positive nasal challenge. Sixty-seven percent (10/15) of those who were either SPT(+) or m-IgE(+) had a positive nasal challenge. SPT or the combination of SPT plus m-IgE performed best in diagnosing mouse allergy. The great majority of mouse-sensitized urban adults with asthma appear to have clinically relevant sensitization. Urban adults with asthma should be evaluated for mouse sensitization using SPT or SPT plus m-IgE testing.

A methodology for the investigation of toughness and crack propagation in mouse bone.

PubMed

Carriero, Alessandra; Zimmermann, Elizabeth A; Shefelbine, Sandra J; Ritchie, Robert O

2014-11-01

Bone fracture is a health concern for those with aged bone and brittle bone diseases. Mouse bone is widely used as a model of human bone, especially to investigate preclinical treatment strategies. However, little is known about the mechanisms of mouse bone fracture and its similarities and differences from fracture in human bone. In this work we present a methodology to investigate the fracture toughness during crack initiation and crack propagation for mouse bone. Mouse femora were dissected, polished on their periosteal surface, notched on the posterior surface at their mid-diaphysis, and tested in three-point bending under displacement control at a rate of 0.1mm/min using an in situ loading stage within an environmental scanning electron microscope. We obtained high-resolution real-time imaging of the crack initiation and propagation in mouse bone. From the images we can measure the crack extension at each step of the crack growth and calculate the toughness of the bone (in terms of stress intensity factor (K) and work to fracture (Wf)) as a function of stable crack length (Δa), thus generating a resistance curve for the mouse bone. The technique presented here provides insight into the evolution of microdamage and the toughening mechanisms that resist crack propagation, which are essential for preclinical development of treatments to enhance bone quality and combat fracture risk. Copyright © 2014 Elsevier Ltd. All rights reserved.

A mouse model for creatine transporter deficiency reveals early onset cognitive impairment and neuropathology associated with brain aging.

PubMed

Baroncelli, Laura; Molinaro, Angelo; Cacciante, Francesco; Alessandrì, Maria Grazia; Napoli, Debora; Putignano, Elena; Tola, Jonida; Leuzzi, Vincenzo; Cioni, Giovanni; Pizzorusso, Tommaso

2016-10-01

Mutations in the creatine (Cr) transporter (CrT) gene lead to cerebral creatine deficiency syndrome-1 (CCDS1), an X-linked metabolic disorder characterized by cerebral Cr deficiency causing intellectual disability, seizures, movement and autistic-like behavioural disturbances, language and speech impairment. Since no data are available about the neural and molecular underpinnings of this disease, we performed a longitudinal analysis of behavioural and pathological alterations associated with CrT deficiency in a CCDS1 mouse model. We found precocious cognitive and autistic-like defects, mimicking the early key features of human CCDS1. Moreover, mutant mice displayed a progressive impairment of short and long-term declarative memory denoting an early brain aging. Pathological examination showed a prominent loss of GABAergic synapses, marked activation of microglia, reduction of hippocampal neurogenesis and the accumulation of autofluorescent lipofuscin. Our data suggest that brain Cr depletion causes both early intellectual disability and late progressive cognitive decline, and identify novel targets to design intervention strategies aimed at overcoming brain CCDS1 alterations. © The Author 2016. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

Nucleotide excision repair deficient mouse models and neurological disease

PubMed Central

Niedernhofer, Laura J.

2008-01-01

Nucleotide excision repair (NER) is a highly conserved mechanism to remove helix-distorting DNA base damage. A major substrate for NER is DNA damage caused by environmental genotoxins, most notably ultraviolet radiation. Xeroderma pigmentosum, Cockayne syndrome and trichothiodystrophy are three human diseases caused by inherited defects in NER. The symptoms and severity of these diseases vary dramatically, ranging from profound developmental delay to cancer predisposition and accelerated aging. All three syndromes include neurological disease, indicating an important role for NER in protecting against spontaneous DNA damage as well. To study the pathophysiology caused by DNA damage, numerous mouse models of NER deficiency were generated by knocking-out genes required for NER or knocking-in disease-causing human mutations. This review explores the utility of these mouse models to study neurological disease caused by NER deficiency. PMID:18272436

The Mouse Tumor Biology Database: A Comprehensive Resource for Mouse Models of Human Cancer.

PubMed

Krupke, Debra M; Begley, Dale A; Sundberg, John P; Richardson, Joel E; Neuhauser, Steven B; Bult, Carol J

2017-11-01

Research using laboratory mice has led to fundamental insights into the molecular genetic processes that govern cancer initiation, progression, and treatment response. Although thousands of scientific articles have been published about mouse models of human cancer, collating information and data for a specific model is hampered by the fact that many authors do not adhere to existing annotation standards when describing models. The interpretation of experimental results in mouse models can also be confounded when researchers do not factor in the effect of genetic background on tumor biology. The Mouse Tumor Biology (MTB) database is an expertly curated, comprehensive compendium of mouse models of human cancer. Through the enforcement of nomenclature and related annotation standards, MTB supports aggregation of data about a cancer model from diverse sources and assessment of how genetic background of a mouse strain influences the biological properties of a specific tumor type and model utility. Cancer Res; 77(21); e67-70. ©2017 AACR . ©2017 American Association for Cancer Research.

Selective Matrix (Hyaluronan) Interaction with CD44 and RhoGTPase Signaling Promotes Keratinocyte Functions and Overcomes Age-related Epidermal Dysfunction

PubMed Central

Bourguignon, Lilly Y.W.; Wong, Gabriel; Xia, Weiliang; Man, Mao-Qiang; Holleran, Walter M.; Elias, Peter M.

2013-01-01

Background Mouse epidermal chronologic aging is closely associated with aberrant matrix (hyaluronan, HA) -size distribution/production and impaired keratinocyte proliferation/differentiation, leading to a marked thinning of the epidermis with functional consequence that causes a slower recovery of permeability barrier function. Objective The goal of this study is to demonstrate mechanism-based, corrective therapeutic strategies using topical applications of small HA (HAS) and/or large HA (HAL) [or a sequential small HA (HAS) and large HA(HAL) (HAs-»HAL) treatment] as well as RhoGTPase signaling perturbation agents to regulate HA/CD44-mediated signaling, thereby restoring normal epidermal function, and permeability barrier homeostasis in aged mouse skin. Methods A number of biochemical, cell biological/molecular, pharmacological and physiological approaches were used to investigate matrix HA-CD44-mediated RhoGTPase signaling in regulating epidermal functions and skin aging. Results In this study we demonstrated that topical application of small HA (HAS) promotes keratinocyte proliferation and increases skin thickness, while it fails to upregulate keratinocyte differentiation or permeability barrier repair in aged mouse skin. In contrast, large HA (HAL) induces only minimal changes in keratinocyte proliferation and skin thickness, but restores keratinocyte differentiation and improves permeability barrier function in aged epidermis. Since neither HAS nor HAL corrects these epidermal defects in aged CD44 knock-out mice, CD44 likely mediates HA-associated epidermal functions in aged mouse skin. Finally, blockade of Rho-kinase activity with Y27632 or protein kinase-Nγ activity with Ro31-8220 significantly decreased the HA (HAS or HAL)-mediated changes in epidermal function in aged mouse skin. Conclusion The results of our study show first that HA application of different sizes regulates epidermal proliferation, differentiation and barrier function in aged mouse skin

Targeting Th17-IL-17 pathway in prevention of micro-invasive prostate cancer in a mouse model

PubMed Central

Zhang, Qiuyang; Liu, Sen; Ge, Dongxia; Cunningham, David M.; Huang, Feng; Ma, Lin; Burris, Thomas P.; You, Zongbing

2017-01-01

Background Chronic inflammation has been associated with the development and progression of human cancers including prostate cancer. The exact role of the inflammatory Th17-IL-17 pathway in prostate cancer remains unknown. In this study, we aimed to determine the importance of Th17 cells and IL-17 in a Pten-null prostate cancer mouse model. Methods The Pten-null mice were treated by Th17 inhibitor SR1001 or anti-mouse IL-17 monoclonal antibody from 6 weeks of age up to 12 weeks of age. For SR1001 treatment, the mice were injected i.p. twice a day with vehicle or SR1001, which was dissolved in a dimethylsulfoxide (DMSO) solution. All mice were euthanized for necropsy at 12 weeks of age. For IL-17 antibody treatment, the mice were injected i.v. once every two weeks with control IgG or rat anti-mouse IL-17 monoclonal antibody, which was dissolved in PBS. The injection time points were at 6, 8, and 10-week-old. All mice were analyzed for the prostate phenotypes at 12 weeks of age. Results We found that either SR1001 or anti-IL-17 antibody treatment decreased the formation of micro-invasive prostate cancer in Pten-null mice. The SR1001 or anti-IL-17 antibody treated mouse prostates had reduced proliferation, increased apoptosis, and reduced angiogenesis, as well as reduced inflammatory cell infiltration. By assessing the epithelial-to-mesenchymal transition (EMT) markers, we found that SR1001 or anti-IL-17 antibody treated prostate tissues had weaker EMT phenotype compared to the control treated prostates. Conclusions These results demonstrated that Th17-IL-17 pathway plays a key role in prostate cancer progression in Pten-null mice. Targeting Th17-IL-17 pathway could prevent micro-invasive prostate cancer formation in mice. PMID:28240383

Influence of abiotic factors on cathemeral activity: the case of Eulemur fulvus collaris in the littoral forest of Madagascar.

PubMed

Donati, Giuseppe; Borgognini-Tarli, Silvana M

2006-01-01

The role environmental factors play in influencing circadian rhythms in natural habitats is still poorly described in primates, especially for those taxa with an activity cycle extended over the 24-hour cycle. In this paper, we elucidate the importance of abiotic factors in entraining the activity of cathemeral primates, focussing on results from a long-term study of Eulemur fulvus collaris (collared brown lemur) in south-eastern Malagasy littoral forest. Two groups of lemurs were followed for 60 whole-day and 59 whole-night observation periods over 14 months. Diurnal and nocturnal observations were equally distributed among moon phases and seasons. Temperature and humidity were recorded hourly by automatic data loggers. The littoral forest has a climatic environment where rainfall and humidity are uncorrelated with temperature and photoperiod. Diurnal and nocturnal activity varied seasonally, with the former increasing significantly with extended day length and the latter increasing significantly with shortened day length. Dusk seemed to act as a primary zeitgeber for these lemurs, coordinating the onset of evening activity throughout the entire year. Lunar phase and the nocturnal luminosity index correlated positively with the duration of nocturnal activity and negatively with the length of diurnal activity. Temperature was positively associated with diurnal activity but did not seem to influence lemur rhythms at night. Finally, lemur nocturnal activity significantly decreased when levels of humidity and rainfall were high. Cathemeral biorhythm is triggered by zeitgebers and influenced by masking factors. The activity of collared brown lemurs appears to be seasonally influenced by photoperiod and directly modulated by nocturnal ambient luminosity. These results are discussed by comparing data from other cathemeral species living in various climatic situations. Copyright (c) 2006 S. Karger AG, Basel.

Primary amines protect against retinal degeneration in mouse models of retinopathies

PubMed Central

Maeda, Akiko; Golczak, Marcin; Chen, Yu; Okano, Kiichiro; Kohno, Hideo; Shiose, Satomi; Ishikawa, Kaede; Harte, William; Palczewska, Grazyna; Maeda, Tadao; Palczewski, Krzysztof

2011-01-01

Vertebrate vision is initiated by photoisomerization of the visual pigment chromophore, 11-cis-retinal, and is maintained by continuous regeneration of this retinoid through a series of reactions termed the retinoid cycle. However, toxic side reaction products, especially those involving reactive aldehyde groups of the photoisomered product, all-trans-retinal, can cause severe retinal pathology. Here we lowered peak concentrations of free all-trans-retinal with primary amine-containing FDA-approved drugs that did not inhibit chromophore regeneration in mouse models of retinal degeneration. Schiff base adducts between all-trans-retinal and these amines were identified by mass spectrometry. Adducts were observed in mouse eyes only when an experimental drug protected the retina from degeneration in both short-term and long-term treatment experiments. This study demonstrates a molecular basis of all-trans-retinal-induced retinal pathology and identifies an assemblage of FDA-approved compounds with protective effects against this pathology in a mouse model that displays features of Stargardt’s and age-related retinal degeneration. PMID:22198730

Inhibition of GLO1 in Glioblastoma Multiforme Increases DNA-AGEs, Stimulates RAGE Expression, and Inhibits Brain Tumor Growth in Orthotopic Mouse Models.

PubMed

Jandial, Rahul; Neman, Josh; Lim, Punnajit P; Tamae, Daniel; Kowolik, Claudia M; Wuenschell, Gerald E; Shuck, Sarah C; Ciminera, Alexandra K; De Jesus, Luis R; Ouyang, Ching; Chen, Mike Y; Termini, John

2018-01-30

Cancers that exhibit the Warburg effect may elevate expression of glyoxylase 1 (GLO1) to detoxify the toxic glycolytic byproduct methylglyoxal (MG) and inhibit the formation of pro-apoptotic advanced glycation endproducts (AGEs). Inhibition of GLO1 in cancers that up-regulate glycolysis has been proposed as a therapeutic targeting strategy, but this approach has not been evaluated for glioblastoma multiforme (GBM), the most aggressive and difficult to treat malignancy of the brain. Elevated GLO1 expression in GBM was established in patient tumors and cell lines using bioinformatics tools and biochemical approaches. GLO1 inhibition in GBM cell lines and in an orthotopic xenograft GBM mouse model was examined using both small molecule and short hairpin RNA (shRNA) approaches. Inhibition of GLO1 with S -( p -bromobenzyl) glutathione dicyclopentyl ester ( p- BrBzGSH(Cp)₂) increased levels of the DNA-AGE N ²-1-(carboxyethyl)-2'-deoxyguanosine (CEdG), a surrogate biomarker for nuclear MG exposure; substantially elevated expression of the immunoglobulin-like receptor for AGEs (RAGE); and induced apoptosis in GBM cell lines. Targeting GLO1 with shRNA similarly increased CEdG levels and RAGE expression, and was cytotoxic to glioma cells. Mice bearing orthotopic GBM xenografts treated systemically with p -BrBzGSH(Cp)₂ exhibited tumor regression without significant off-target effects suggesting that GLO1 inhibition may have value in the therapeutic management of these drug-resistant tumors.

Inhibition of GLO1 in Glioblastoma Multiforme Increases DNA-AGEs, Stimulates RAGE Expression, and Inhibits Brain Tumor Growth in Orthotopic Mouse Models

PubMed Central

Jandial, Rahul; Neman, Josh; Tamae, Daniel; Kowolik, Claudia M.; Wuenschell, Gerald E.; Ciminera, Alexandra K.; De Jesus, Luis R.; Ouyang, Ching; Chen, Mike Y.

2018-01-01

Cancers that exhibit the Warburg effect may elevate expression of glyoxylase 1 (GLO1) to detoxify the toxic glycolytic byproduct methylglyoxal (MG) and inhibit the formation of pro-apoptotic advanced glycation endproducts (AGEs). Inhibition of GLO1 in cancers that up-regulate glycolysis has been proposed as a therapeutic targeting strategy, but this approach has not been evaluated for glioblastoma multiforme (GBM), the most aggressive and difficult to treat malignancy of the brain. Elevated GLO1 expression in GBM was established in patient tumors and cell lines using bioinformatics tools and biochemical approaches. GLO1 inhibition in GBM cell lines and in an orthotopic xenograft GBM mouse model was examined using both small molecule and short hairpin RNA (shRNA) approaches. Inhibition of GLO1 with S-(p-bromobenzyl) glutathione dicyclopentyl ester (p-BrBzGSH(Cp)2) increased levels of the DNA-AGE N2-1-(carboxyethyl)-2′-deoxyguanosine (CEdG), a surrogate biomarker for nuclear MG exposure; substantially elevated expression of the immunoglobulin-like receptor for AGEs (RAGE); and induced apoptosis in GBM cell lines. Targeting GLO1 with shRNA similarly increased CEdG levels and RAGE expression, and was cytotoxic to glioma cells. Mice bearing orthotopic GBM xenografts treated systemically with p-BrBzGSH(Cp)2 exhibited tumor regression without significant off-target effects suggesting that GLO1 inhibition may have value in the therapeutic management of these drug-resistant tumors. PMID:29385725

The Role of Apolipoprotein E and Ethanol Exposure in Age-Related Changes in Choline Acetyltransferase and Brain-Derived Neurotrophic Factor Expression in the Mouse Hippocampus.

PubMed

Jamal, Mostofa; Ito, Asuka; Tanaka, Naoko; Miki, Takanori; Takakura, Ayaka; Suzuki, Shingo; Ameno, Kiyoshi; Kinoshita, Hiroshi

2018-05-01

Disruption of apolipoprotein E (APOE) is responsible for age-dependent neurodegeneration and cognitive impairment. Elderly individuals are more sensitive than young individuals to the effects of ethanol (EtOH), particularly those affecting cognition. We investigated the role of APOE deficiency and EtOH exposure on age-dependent alterations in choline acetyltransferase (ChAT) and brain-derived neurotrophic factor (BDNF) mRNA and protein expression in the mouse hippocampus. Three-month-old (young) and 12-month-old (aged) ApoE-knockout (ApoE-KO) and wild-type (WT) mice were treated with saline or 2 g/kg EtOH, and the bilateral hippocampus was collected after 60 min for real-time PCR and western blotting analyses. ChAT (P < 0.01) and BDNF (P < 0.01) expression were significantly decreased in both young and aged saline- and EtOH-treated ApoE-KO mice versus young and aged saline- and EtOH-treated WT mice. Aged saline- and EtOH-treated ApoE-KO mice exhibited greater differences in ChAT and BDNF expression (P < 0.01) than young saline- and EtOH-treated ApoE-KO mice. Aged EtOH-treated WT mice also exhibited larger decreases in BDNF expression (P < 0.01)-but not in ChAT expression-than young EtOH-treated WT mice. EtOH decreased ChAT and BDNF expression in both young (P < 0.01) and aged (P < 0.01) ApoE-KO mice versus EtOH-free ApoE-KO mice of the same age. EtOH also decreased BDNF expression in aged (P < 0.01) WT mice versus EtOH-free aged WT mice. In summary, these results suggest that APOE deficiency and EtOH exposure cause age-dependent decreases in ChAT and BDNF in the hippocampus. Importantly, the decreases in ChAT and BDNF were greater in aged EtOH-treated mice, particularly those lacking APOE, raising the possibility that APOE-deficient individuals who consume alcohol may be at greater risk of memory deficit.

Accelerated renal disease is associated with the development of metabolic syndrome in a glucolipotoxic mouse model

PubMed Central

Martínez-García, Cristina; Izquierdo, Adriana; Velagapudi, Vidya; Vivas, Yurena; Velasco, Ismael; Campbell, Mark; Burling, Keith; Cava, Fernando; Ros, Manuel; Orešič, Matej; Vidal-Puig, Antonio; Medina-Gomez, Gema

2012-01-01

SUMMARY Individuals with metabolic syndrome are at high risk of developing chronic kidney disease (CKD) through unclear pathogenic mechanisms. Obesity and diabetes are known to induce glucolipotoxic effects in metabolically relevant organs. However, the pathogenic role of glucolipotoxicity in the aetiology of diabetic nephropathy is debated. We generated a murine model, the POKO mouse, obtained by crossing the peroxisome proliferator-activated receptor gamma 2 (PPARγ2) knockout (KO) mouse into a genetically obese ob/ob background. We have previously shown that the POKO mice showed: hyperphagia, insulin resistance, hyperglycaemia and dyslipidaemia as early as 4 weeks of age, and developed a complete loss of normal β-cell function by 16 weeks of age. Metabolic phenotyping of the POKO model has led to investigation of the structural and functional changes in the kidney and changes in blood pressure in these mice. Here we demonstrate that the POKO mouse is a model of renal disease that is accelerated by high levels of glucose and lipid accumulation. Similar to ob/ob mice, at 4 weeks of age these animals exhibited an increased urinary albumin:creatinine ratio and significantly increased blood pressure, but in contrast showed a significant increase in the renal hypertrophy index and an associated increase in p27Kip1 expression compared with their obese littermates. Moreover, at 4 weeks of age POKO mice showed insulin resistance, an alteration of lipid metabolism and glomeruli damage associated with increased transforming growth factor beta (TGFβ) and parathyroid hormone-related protein (PTHrP) expression. At this age, levels of proinflammatory molecules, such as monocyte chemoattractant protein-1 (MCP-1), and fibrotic factors were also increased at the glomerular level compared with levels in ob/ob mice. At 12 weeks of age, renal damage was fully established. These data suggest an accelerated lesion through glucolipotoxic effects in the renal pathogenesis in POKO mice

Accelerated renal disease is associated with the development of metabolic syndrome in a glucolipotoxic mouse model.

PubMed

Martínez-García, Cristina; Izquierdo, Adriana; Velagapudi, Vidya; Vivas, Yurena; Velasco, Ismael; Campbell, Mark; Burling, Keith; Cava, Fernando; Ros, Manuel; Oresic, Matej; Vidal-Puig, Antonio; Medina-Gomez, Gema

2012-09-01

Individuals with metabolic syndrome are at high risk of developing chronic kidney disease (CKD) through unclear pathogenic mechanisms. Obesity and diabetes are known to induce glucolipotoxic effects in metabolically relevant organs. However, the pathogenic role of glucolipotoxicity in the aetiology of diabetic nephropathy is debated. We generated a murine model, the POKO mouse, obtained by crossing the peroxisome proliferator-activated receptor gamma 2 (PPARγ2) knockout (KO) mouse into a genetically obese ob/ob background. We have previously shown that the POKO mice showed: hyperphagia, insulin resistance, hyperglycaemia and dyslipidaemia as early as 4 weeks of age, and developed a complete loss of normal β-cell function by 16 weeks of age. Metabolic phenotyping of the POKO model has led to investigation of the structural and functional changes in the kidney and changes in blood pressure in these mice. Here we demonstrate that the POKO mouse is a model of renal disease that is accelerated by high levels of glucose and lipid accumulation. Similar to ob/ob mice, at 4 weeks of age these animals exhibited an increased urinary albumin:creatinine ratio and significantly increased blood pressure, but in contrast showed a significant increase in the renal hypertrophy index and an associated increase in p27(Kip1) expression compared with their obese littermates. Moreover, at 4 weeks of age POKO mice showed insulin resistance, an alteration of lipid metabolism and glomeruli damage associated with increased transforming growth factor beta (TGFβ) and parathyroid hormone-related protein (PTHrP) expression. At this age, levels of proinflammatory molecules, such as monocyte chemoattractant protein-1 (MCP-1), and fibrotic factors were also increased at the glomerular level compared with levels in ob/ob mice. At 12 weeks of age, renal damage was fully established. These data suggest an accelerated lesion through glucolipotoxic effects in the renal pathogenesis in POKO mice.

Dissecting Alzheimer disease in Down syndrome using mouse models

PubMed Central

Choong, Xun Yu; Tosh, Justin L.; Pulford, Laura J.; Fisher, Elizabeth M. C.

2015-01-01

Down syndrome (DS) is a common genetic condition caused by the presence of three copies of chromosome 21 (trisomy 21). This greatly increases the risk of Alzheimer disease (AD), but although virtually all people with DS have AD neuropathology by 40 years of age, not all develop dementia. To dissect the genetic contribution of trisomy 21 to DS phenotypes including those relevant to AD, a range of DS mouse models has been generated which are trisomic for chromosome segments syntenic to human chromosome 21. Here, we consider key characteristics of human AD in DS (AD-DS), and our current state of knowledge on related phenotypes in AD and DS mouse models. We go on to review important features needed in future models of AD-DS, to understand this type of dementia and so highlight pathogenic mechanisms relevant to all populations at risk of AD. PMID:26528151

Dissecting Alzheimer disease in Down syndrome using mouse models.

PubMed

Choong, Xun Yu; Tosh, Justin L; Pulford, Laura J; Fisher, Elizabeth M C

2015-01-01

Down syndrome (DS) is a common genetic condition caused by the presence of three copies of chromosome 21 (trisomy 21). This greatly increases the risk of Alzheimer disease (AD), but although virtually all people with DS have AD neuropathology by 40 years of age, not all develop dementia. To dissect the genetic contribution of trisomy 21 to DS phenotypes including those relevant to AD, a range of DS mouse models has been generated which are trisomic for chromosome segments syntenic to human chromosome 21. Here, we consider key characteristics of human AD in DS (AD-DS), and our current state of knowledge on related phenotypes in AD and DS mouse models. We go on to review important features needed in future models of AD-DS, to understand this type of dementia and so highlight pathogenic mechanisms relevant to all populations at risk of AD.

Caspase-6 activity in the CA1 region of the hippocampus induces age-dependent memory impairment

PubMed Central

LeBlanc, A C; Ramcharitar, J; Afonso, V; Hamel, E; Bennett, D A; Pakavathkumar, P; Albrecht, S

2014-01-01

Active Caspase-6 is abundant in the neuropil threads, neuritic plaques and neurofibrillary tangles of Alzheimer disease brains. However, its contribution to the pathophysiology of Alzheimer disease is unclear. Here, we show that higher levels of Caspase-6 activity in the CA1 region of aged human hippocampi correlate with lower cognitive performance. To determine whether Caspase-6 activity, in the absence of plaques and tangles, is sufficient to cause memory deficits, we generated a transgenic knock-in mouse that expresses a self-activated form of human Caspase-6 in the CA1. This Caspase-6 mouse develops age-dependent spatial and episodic memory impairment. Caspase-6 induces neuronal degeneration and inflammation. We conclude that Caspase-6 activation in mouse CA1 neurons is sufficient to induce neuronal degeneration and age-dependent memory impairment. These results indicate that Caspase-6 activity in CA1 could be responsible for the lower cognitive performance of aged humans. Consequently, preventing or inhibiting Caspase-6 activity in the aged may provide an efficient novel therapeutic approach against Alzheimer disease. PMID:24413155

Phospholipid epitopes for mouse antibodies against bromelain-treated mouse erythrocytes.

PubMed Central

Kawaguchi, S

1987-01-01

The reactivity of mouse antibodies against bromelain-treated mouse erythrocytes (BrMRBC) with phospholipid epitopes was assessed by ELISA, using four clones of monoclonal anti-BrMRBC antibodies that had idiotypes distinct from one another. The four antibodies could bind to low-density lipoproteins (LDL) from human and chicken, but not to LDL from mouse and rat. As to liposomes of natural phospholipids, all the clones reacted with liposomes of phosphatidylcholine, and some of them could react with liposomes of sphingomyelin, phosphatidylglycerol, phosphatidylic acid or cardiolipin. For liposomes of synthetic phosphatidylcholine with different fatty acids, the length of carbon chains and the number of unsaturated carbon chains of the fatty acids markedly affected the binding of each monoclonal antibody to the liposomes. The addition of dicetyl phosphate or stearylamine to phosphatidylcholine liposomes changed the reactivity of the liposomes. These results support the view that mouse anti-BrMRBC antibodies can recognize appropriately spaced phosphorylcholine residues on the surface of phospholipid liposomes, LDL and cells. The four clones had similar capacities for binding to LDL as well as to BrMRBC, but they had obviously different capacities for binding to phospholipid liposomes; the epitopes on phospholipid liposomes used in the present study were not so perfect as to react well with every anti-BrMRBC antibody. PMID:2443446

Aging and unusual catecholamine-containing structures in the mouse brain.

PubMed

Masuoka, D T; Jonsson, G; Finch, C E

1979-06-22

Brains of C57BL/6J mice, aged 4, 8 and 20--29 months, were examined by the Falck-Hillarp histochemical fluorescence technique. Numerous large, intensely fluorescent green to yellow-green spots (LIFS) were observed in the brains of senescent mice. LIFS were generally round to ovoid in shape and ranged in size from about 10 micrometer to about 30 micrometer. Histochemical and pharmacological procedures and spectral analysis indicated that the formaldehyde-induced fluorescence of the LIFS was due to the presence of catecholamines (CA) rather than aging pigment. Their distribution in the brain suggests an association with nerve axons or terminals rather than cell bodies. The number of LIFS in the hypothalamus increased progressively during aging. It is proposed that LIFS may represent age-related, unusual CA accumulation in enlargements proximal to axonal or terminal portions undergoing spontaneous degeneration.

Regenerative hair waves in aging mice and extra-follicular modulators follistatin, dkk1, and sfrp4.

PubMed

Chen, Chih-Chiang; Murray, Philip J; Jiang, Ting Xin; Plikus, Maksim V; Chang, Yun-Ting; Lee, Oscar K; Widelitz, Randall B; Chuong, Cheng-Ming

2014-08-01

Hair cycling is modulated by factors both intrinsic and extrinsic to hair follicles. Cycling defects lead to conditions such as aging-associated alopecia. Recently, we demonstrated that mouse skin exhibits regenerative hair waves, reflecting a coordinated regenerative behavior in follicle populations. Here, we use this model to explore the regenerative behavior of aging mouse skin. Old mice (>18 months) tracked over several months show that with progressing age, hair waves slow down, wave propagation becomes restricted, and hair cycle domains fragment into smaller domains. Transplanting aged donor mouse skin to a young host can restore donor cycling within a 3 mm range of the interface, suggesting that changes are due to extracellular factors. Therefore, hair stem cells in aged skin can be reactivated. Molecular studies show that extra-follicular modulators Bmp2, Dkk1, and Sfrp4 increase in early anagen. Further, we identify follistatin as an extra-follicular modulator, which is highly expressed in late telogen and early anagen. Indeed, follistatin induces hair wave propagation and its level decreases in aging mice. We present an excitable medium model to simulate the cycling behavior in aging mice and illustrate how the interorgan macroenvironment can regulate the aging process by integrating both "activator" and "inhibitor" signals.

A new mouse model of metabolic syndrome and associated complications

PubMed Central

Wang, Yun; Zheng, Yue; Nishina, Patsy M; Naggert, Jürgen K.

2010-01-01

Metabolic Syndrome (MS) encompasses a clustering of risk factors for cardiovascular disease, including obesity, insulin resistance, and dyslipidemia. We characterized a new mouse model carrying a dominant mutation, C57BL/6J-Nmf15/+ (B6-Nmf15/+), which develops additional complications of MS such as adipose tissue inflammation and cardiomyopathy. A backcross was used to genetically map the Nmf15 locus. Mice were examined in the CLAMS™ animal monitoring system, and dual energy X-ray absorptiometry and blood chemistry analyses were performed. Hypothalamic LepR, SOCS1 and STAT3 phosphorylation were examined. Cardiac function was assessed by Echo- and Electro Cardiography. Adipose tissue inflammation was characterized by in situ hybridization and measurement of Jun kinase activity. The Nmf15 locus mapped to distal mouse chromosome 5 with a LOD score of 13.8. Nmf15 mice developed obesity by 12 weeks of age. Plasma leptin levels were significantly elevated in pre-obese Nmf15 mice at 8 weeks of age and an attenuated STAT3 phosphorylation in the hypothalamus suggests a primary leptin resistance. Adipose tissue from Nmf15 mice showed a remarkable degree of inflammation and macrophage infiltration as indicated by expression of the F4/80 marker and increased phosphorylation of JNK1/2. Lipidosis was observed in tubular epithelial cells and glomeruli of the kidney. Nmf15 mice demonstrate both histological and pathophysiological evidence of cardiomyopathy. The Nmf15 mouse model provides a new entry point into pathways mediating leptin resistance and obesity. It is one of few models that combine many aspects of metabolic syndrome and can be useful for testing new therapeutic approaches for combating obesity complications, particularly cardiomyopathy. PMID:19398498

Axial nonuniformity of geometric and mechanical properties of mouse aorta is increased during postnatal growth.

PubMed

Huang, Yi; Guo, Xiaomei; Kassab, Ghassan S

2006-02-01

The hemodynamic conditions of aorta are relatively uniform prenatally and become more heterogeneous postnatally. Our objective was to quantify the heterogeneity of geometry and mechanical properties during growth and development. To accomplish this objective, we obtained a systematic set of data on the geometry and mechanical properties along the length of mouse aorta during postnatal development. C57BL/6 mice of ages 1-33 days were studied. The ascending aorta was cannulated in situ and preconditioned with several cyclic changes in pressure. We investigated the axial variations of geometry (diameter and length) and mechanical properties (stress-stain relation, elastic modulus and compliance) of the mouse aorta from the aortic valve to the common iliac. Our results show that the arterial blood pressure of mice increased from approximately 30 to 80 mmHg during the first 2 wk of life. The stretch ratio, diameter, wall (intima-media) thickness, and total lumen volume of mouse aorta increased with age. The aorta was transformed from a cylindrical tube at birth to a tapered structure during growth. Furthermore, we found the mechanical properties were fairly uniform along the length of the aorta at birth and become more nonuniform with age. We conclude that the rapid change of blood pressure and blood flow after birth alter the geometric and mechanical properties differentially along the length of the aorta. Hence, the axial nonuniformity of the aorta increases as the organ becomes more specialized during growth and development.

Ultrasound biomicroscopy in mouse cardiovascular development

NASA Astrophysics Data System (ADS)

Turnbull, Daniel H.

2004-05-01

The mouse is the preferred animal model for studying mammalian cardiovascular development and many human congenital heart diseases. Ultrasound biomicroscopy (UBM), utilizing high-frequency (40-50-MHz) ultrasound, is uniquely capable of providing in vivo, real-time microimaging and Doppler blood velocity measurements in mouse embryos and neonates. UBM analyses of normal and abnormal mouse cardiovascular function will be described to illustrate the power of this microimaging approach. In particular, real-time UBM images have been used to analyze dimensional changes in the mouse heart from embryonic to neonatal stages. UBM-Doppler has been used recently to examine the precise timing of onset of a functional circulation in early-stage mouse embryos, from the first detectable cardiac contractions. In other experiments, blood velocity waveforms have been analyzed to characterize the functional phenotype of mutant mouse embryos having defects in cardiac valve formation. Finally, UBM has been developed for real-time, in utero image-guided injection of mouse embryos, enabling cell transplantation and genetic gain-of-function experiments with transfected cells and retroviruses. In summary, UBM provides a unique and powerful approach for in vivo analysis and image-guided manipulation in normal and genetically engineered mice, over a wide range of embryonic to neonatal developmental stages.

Walking with Grandfather and Great Wolf and Little Mouse Sister. Teacher's Guide.

ERIC Educational Resources Information Center

Lethbridge Univ. (Alberta).

Written for use with videotaped versions of the stories "Walking with Grandfather" and "Great Wolf and Little Mouse Sister," this guide presents 20 lessons that teachers can adapt for students of various ages and use in integrated units or other curriculum approaches. The introductory material describes the use and philosophy of the video stories,…

Cerebral amyloid-beta protein accumulation with aging in cotton-top tamarins: a model of early Alzheimer's disease?

PubMed

Lemere, Cynthia A; Oh, Jiwon; Stanish, Heather A; Peng, Ying; Pepivani, Imelda; Fagan, Anne M; Yamaguchi, Haruyasu; Westmoreland, Susan V; Mansfield, Keith G

2008-04-01

Alzheimer's disease (AD) is the most common progressive form of dementia in the elderly. Two major neuropathological hallmarks of AD include cerebral deposition of amyloid-beta protein (Abeta) into plaques and blood vessels, and the presence of neurofibrillary tangles in brain. In addition, activated microglia and reactive astrocytes are often associated with plaques and tangles. Numerous other proteins are associated with plaques in human AD brain, including Apo E and ubiquitin. The amyloid precursor protein and its shorter fragment, Abeta, are homologous between humans and non-human primates. Cerebral Abeta deposition has been reported previously for rhesus monkeys, vervets, squirrel monkeys, marmosets, lemurs, cynomologous monkeys, chimpanzees, and orangutans. Here we report, for the first time, age-related neuropathological changes in cotton-top tamarins (CTT, Saguinus oedipus), an endangered non-human primate native to the rainforests of Colombia and Costa Rica. Typical lifespan is 13-14 years of age in the wild and 15-20+ years in captivity. We performed detailed immunohistochemical analyses of Abeta deposition and associated pathogenesis in archived brain sections from 36 tamarins ranging in age from 6-21 years. Abeta plaque deposition was observed in 16 of the 20 oldest tamarins (>12 years). Plaques contained mainly Abeta42, and in the oldest animals, were associated with reactive astrocytes, activated microglia, Apo E, and ubiquitin-positive dystrophic neurites, similar to human plaques. Vascular Abeta was detected in 14 of the 20 aged tamarins; Abeta42 preceded Abeta40 deposition. Phospho-tau labeled dystrophic neurites and tangles, typically present in human AD, were absent in the tamarins. In conclusion, tamarins may represent a model of early AD pathology.

Cortical mechanics and myosin-II abnormalities associated with post-ovulatory aging: implications for functional defects in aged eggs

PubMed Central

Mackenzie, Amelia C.L.; Kyle, Diane D.; McGinnis, Lauren A.; Lee, Hyo J.; Aldana, Nathalia; Robinson, Douglas N.; Evans, Janice P.

2016-01-01

STUDY HYPOTHESIS Cellular aging of the egg following ovulation, also known as post-ovulatory aging, is associated with aberrant cortical mechanics and actomyosin cytoskeleton functions. STUDY FINDING Post-ovulatory aging is associated with dysfunction of non-muscle myosin-II, and pharmacologically induced myosin-II dysfunction produces some of the same deficiencies observed in aged eggs. WHAT IS KNOWN ALREADY Reproductive success is reduced with delayed fertilization and when copulation or insemination occurs at increased times after ovulation. Post-ovulatory aged eggs have several abnormalities in the plasma membrane and cortex, including reduced egg membrane receptivity to sperm, aberrant sperm-induced cortical remodeling and formation of fertilization cones at the site of sperm entry, and reduced ability to establish a membrane block to prevent polyspermic fertilization. STUDY DESIGN, SAMPLES/MATERIALS, METHODS Ovulated mouse eggs were collected at 21–22 h post-human chorionic gonadotrophin (hCG) (aged eggs) or at 13–14 h post-hCG (young eggs), or young eggs were treated with the myosin light chain kinase (MLCK) inhibitor ML-7, to test the hypothesis that disruption of myosin-II function could mimic some of the effects of post-ovulatory aging. Eggs were subjected to various analyses. Cytoskeletal proteins in eggs and parthenogenesis were assessed using fluorescence microscopy, with further analysis of cytoskeletal proteins in immunoblotting experiments. Cortical tension was measured through micropipette aspiration assays. Egg membrane receptivity to sperm was assessed in in vitro fertilization (IVF) assays. Membrane topography was examined by low-vacuum scanning electron microscopy (SEM). MAIN RESULTS AND THE ROLE OF CHANCE Aged eggs have decreased levels and abnormal localizations of phosphorylated myosin-II regulatory light chain (pMRLC; P = 0.0062). Cortical tension, which is mediated in part by myosin-II, is reduced in aged mouse eggs when compared with

A paraxial schematic eye model for the growing C57BL/6 mouse.

PubMed

Schmucker, Christine; Schaeffel, Frank

2004-01-01

The mouse eye has potential to become an important model for studies on the genetic control of eye growth and myopia. However, no data are published on the development of its optical properties. We developed a paraxial schematic model of the growing eye for the most common laboratory mouse strain, the C57BL/6 mouse, for the age range between 22 and 100 days. Refractive development was followed with eccentric infrared photorefraction and corneal curvature with infrared photokeratometry. To measure ocular dimensions, freshly excised eyes were immediately frozen after enucleation to minimize distortions. Eyes were cut with a cryostat down to the bisecting horizontal plane, until the optic nerve head became visible. The standard deviations were +/-10 microm for repeated measurements in highly magnified videographs, taken in several section planes close to the equator in the same eyes. To evaluate inter-eye and inter-individual variability, a total of 20 mice (34 eyes) were studied, with 3-4 eyes for each of the 9 sampling ages. Schematic eye models were developed using paraxial ray tracing software (OSLO, LT Lambda Research Corporation, and a self-written program). The measured refractive errors were initially +4.0+/-0.6 D at approximately 30 days, and levelled off with +7.0+/-2.5 D at about 70 days. Corneal radius of curvature did not change with age (1.414+/-0.019 mm). Both axial lens diameter and axial eye length grew linearly (regression equations: lens, 1619 microm +5.5 microm/day, R=0.916; axial length, 2899 microm +4.4 microm/day, R=0.936). The lens grew so fast that vitreous chamber depth declined with age (regression equation: 896 microm -3.2 microm/day, R=0.685). The radii of curvature of the anterior lens surface increased during development (from 0.982 mm at day 22 to 1.208 mm at day 100), whereas the radii of the posterior lens surface remained constant (-1.081+/-0.054 mm). The calculated homogeneous lens index increased linearly with age (from 1.568 to 1

C/EBPβ regulates delta-secretase expression and mediates pathogenesis in mouse models of Alzheimer's disease.

PubMed

Wang, Zhi-Hao; Gong, Ke; Liu, Xia; Zhang, Zhentao; Sun, Xiaoou; Wei, Zheng Zachory; Yu, Shan Ping; Manfredsson, Fredric P; Sandoval, Ivette M; Johnson, Peter F; Jia, Jianping; Wang, Jian-Zhi; Ye, Keqiang

2018-05-03

Delta-secretase cleaves both APP and Tau to mediate the formation of amyloid plaques and neurofibrillary tangle in Alzheimer's disease (AD). However, how aging contributes to an increase in delta-secretase expression and AD pathologies remains unclear. Here we show that a CCAAT-enhancer-binding protein (C/EBPβ), an inflammation-regulated transcription factor, acts as a key age-dependent effector elevating both delta-secretase (AEP) and inflammatory cytokines expression in mediating pathogenesis in AD mouse models. We find that C/EBPβ regulates delta-secretase transcription and protein levels in an age-dependent manner. Overexpression of C/EBPβ in young 3xTg mice increases delta-secretase and accelerates the pathological features including cognitive dysfunctions, which is abolished by inactive AEP C189S. Conversely, depletion of C/EBPβ from old 3xTg or 5XFAD mice diminishes delta-secretase and reduces AD pathologies, leading to amelioration of cognitive impairment in these AD mouse models. Thus, our findings support that C/EBPβ plays a pivotal role in AD pathogenesis via increasing delta-secretase expression.

Immunotherapy for choroidal neovascularization in a laser-induced mouse model simulating exudative (wet) macular degeneration

NASA Astrophysics Data System (ADS)

Bora, Puran S.; Hu, Zhiwei; Tezel, Tongalp H.; Sohn, Jeong-Hyeon; Kang, Shin Goo; Cruz, Jose M. C.; Bora, Nalini S.; Garen, Alan; Kaplan, Henry J.

2003-03-01

Age-related macular degeneration (AMD) is the leading cause of blindness after age 55 in the industrialized world. Severe loss of central vision frequently occurs with the exudative (wet) form of AMD, as a result of the formation of a pathological choroidal neovasculature (CNV) that damages the macular region of the retina. We tested the effect of an immunotherapy procedure, which had been shown to destroy the pathological neovasculature in solid tumors, on the formation of laser-induced CNV in a mouse model simulating exudative AMD in humans. The procedure involves administering an Icon molecule that binds with high affinity and specificity to tissue factor (TF), resulting in the activation of a potent cytolytic immune response against cells expressing TF. The Icon binds selectively to TF on the vascular endothelium of a CNV in the mouse and pig models and also on the CNV of patients with exudative AMD. Here we show that the Icon dramatically reduces the frequency of CNV formation in the mouse model. After laser treatment to induce CNV formation, the mice were injected either with an adenoviral vector encoding the Icon, resulting in synthesis of the Icon by vector-infected mouse cells, or with the Icon protein. The route of injection was i.v. or intraocular. The efficacy of the Icon in preventing formation of laser-induced CNV depends on binding selectively to the CNV. Because the Icon binds selectively to the CNV in exudative AMD as well as to laser-induced CNV, the Icon might also be efficacious for treating patients with exudative AMD.

Wnt/B-Catenin Signaling is Required to Rescue Midbrain Dopaminergic Progenitors and Promote Neurorepair in Ageing Mouse Model of Parkinson’s Disease

PubMed Central

L’Episcopo, Francesca; Tirolo, Cataldo; Testa, Nunzio; Caniglia, Salvatore; Morale, Maria Concetta; Serapide, Maria Francesca; Pluchino, Stefano; Marchetti, Bianca

2014-01-01

SUMMARY Wnt/β-catenin signaling is required for specification and neurogenesis of midbrain dopaminergic (mDA) neurons, the pivotal neuronal population that degenerates in Parkinson’s disease (PD) and in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) mouse model of PD. Wnt/β-catenin signaling plays a vital role in adult neurogenesis but whether it might engage DA neurogenesis/neurorepair in the affected PD brain is yet unresolved. Recently, the adult midbrain aqueduct periventricular regions (Aq-PVRs) were shown to harbor neural stem/progenitor cells (mNPCs) with DA potential in vitro, but restrictive mechanisms in vivo are believed to limit their DA regenerative capacity. Using in vitro mNPC culture systems we herein demonstrate that aging is one most critical factor restricting mNPC neurogenic potential via dysregulation of Wnt/β-catenin signaling. Cococulture paradigms between young/aged (Y/A) mNPCs and Y/A astrocytes identified glial age and a decline of glial-derived factors including Wnts as key determinants of impaired neurogenic potential, whereas Wnt activation regimens efficiently reversed the diminished proliferative, neuronal and DA differentiation potential of A-mNPCs. Next, in vivo studies in wild (Wt) and transgenic β-catenin reporter mice uncovered Wnt/β-catenin signaling activation and remarkable astrocyte remodeling of Aq-PVR in response to MPTP-induced DA neuron death. Spatio-temporal analyses unveiled β-catenin signaling in predopaminergic (Nurr1+/TH−) and imperiled or rescuing DAT+ neurons during MPTP-induced DA neuron injury and self-repair. Aging inhibited Wnt signaling, whereas β-catenin activation in situ with a specific GSK-3β antagonist promoted a significant degree of DA neurorestoration associated with reversal of motor deficit, with implications for neurorestorative approaches in PD. PMID:24648001

Transposable elements become active and mobile in the genomes of aging mammalian somatic tissues.

PubMed

De Cecco, Marco; Criscione, Steven W; Peterson, Abigail L; Neretti, Nicola; Sedivy, John M; Kreiling, Jill A

2013-12-01

Transposable elements (TEs) were discovered by Barbara McClintock in maize and have since been found to be ubiquitous in all living organisms. Transposition is mutagenic and organisms have evolved mechanisms to repress the activity of their endogenous TEs. Transposition in somatic cells is very low, but recent evidence suggests that it may be derepressed in some cases, such as cancer development. We have found that during normal aging several families of retrotransposable elements (RTEs) start being transcribed in mouse tissues. In advanced age the expression culminates in active transposition. These processes are counteracted by calorie restriction (CR), an intervention that slows down aging. Retrotransposition is also activated in age-associated, naturally occurring cancers in the mouse. We suggest that somatic retrotransposition is a hitherto unappreciated aging process. Mobilization of RTEs is likely to be an important contributor to the progressive dysfunction of aging cells.

Effect of reproductive ageing on pregnant mouse uterus and cervix

PubMed Central

Patel, Rima; Moffatt, James D.; Mourmoura, Evangelia; Demaison, Luc; Seed, Paul T.; Poston, Lucilla

2017-01-01

Key points Older pregnant women have a greater risk of operative delivery, still birth and post‐term induction.This suggests that maternal age can influence the timing of birth and processes of parturition.We have found that increasing maternal age in C57BL/6J mice is associated with prolongation of gestation and length of labour.Older pregnant mice also had delayed progesterone withdrawal and impaired myometrial function.Uterine ageing and labour dysfunction should be investigated further in older primigravid women. Abstract Advanced maternal age (≥35 years) is associated with increased rates of operative delivery, stillbirth and post‐term labour induction. The physiological causes remain uncertain, although impaired myometrial function has been implicated. To investigate the hypothesis that maternal age directly influences successful parturition, we assessed the timing of birth and fetal outcome in pregnant C57BL/6J mice at 3 months (young) and 5 months (intermediate) vs. 8 months (older) of age using infrared video recording. Serum progesterone profiles, myometrium and cervix function, and mitochondrial electron transport chain complex enzymatic activities were also examined. Older pregnant mice had a longer mean gestation and labour duration (P < 0.001), as well as reduced litter size (P < 0.01) vs. 3‐month‐old mice. Older mice did not exhibit the same decline in serum progesterone concentrations as younger mice. Cervical tissues from older mice were more distensible than younger mice (P < 0.05). Oxytocin receptor and connexin‐43 mRNA expression were reduced in the myometrium from 8‐month‐old vs. 3‐month‐old mice (P < 0.05 and P < 0.01 respectively) in tandem with more frequent but shorter duration spontaneous myometrial contractions (P < 0.05) and an attenuated contractile response to oxytocin. Myometrial mitochondrial copy number was reduced in older mice, although there were no age‐induced changes to the enzymatic

Selective Neurodegeneration, Without Neurofibrillary Tangles, in a Mouse Model of Niemann-Pick C Disease

PubMed Central

German, Dwight C.; Quintero, E. Matthew; Liang, Chang-Lin; Ng, Benton; Punia, Surender; Xie, Chonglun; Dietschy, John M.

2012-01-01

The BALB/c mouse model of Niemann-Pick type C (NPC) disease exhibits neuropathological similarities to the human condition. There is an age-related cerebral atrophy, demyelination of the corpus callosum, and degeneration of cerebellar Purkinje cells in the NPC mouse. In human NPC, many cortical and subcortical neurons contain neurofibrillary tangles, which are thought by some investigators to play an important role in the neurodegenerative process. The purpose of the present study was to determine whether neurodegeneration occurs in the NPC mouse, in brain regions other than the cerebellum and whether the degeneration is related to the presence of neurofibrillary tangles. Using light microscopic methods with immunohistochemistry, electron microscopy, and cell counting methods, 11-week-old NPC+/+ and NPC−/− animals were examined. In the NPC−/− mice, there were 96% fewer Purkinje cells, 28% fewer neurons in the prefrontal cortex, 20% fewer neurons in the thalamus, and 63% fewer glial cells in the corpus callosum. On the other hand, previous studies indicate normal numbers of neurons and glial cells in these same neuroanatomical regions in young NPC−/− mice. There were normal numbers of cholinergic neurons in sections assessed in the striatum and basal forebrain in the 11-week-old animals and no evidence of neurofibrillary tangles within cells. The present data indicate that both neurons and glial cells die in the NPC mouse but that all cells are not equally vulnerable. There was no evidence for neurofibrillary tangles in the NPC mouse, and therefore the degenerative process in the mouse is unrelated to the neurofibrillary tangle. PMID:11298365

Microvasculature remodeling in the mouse lower gut during inflammaging

PubMed Central

Jeong, Jae-Ho; Kim, KwangSoo; Lim, Daejin; Kim, Kun-Hee; Kim, Hyung-Seok; Lee, Sungsu; Song, Joo-Hye; Moon, Byoung-Gon; Choy, Hyon E.; Park, Sang Chul

2017-01-01

Inflammaging is defined as low-grade, chronic, systemic inflammation in aging, in the absence of overt infection. Age-associated deterioration of gastrointestinal function could be ascribed to the inflammaging, although evidence is yet to emerge. Here we show that microvessels in aging mouse intestine were progressively deprived of supportive structures, microvessel-associated pericytes and adherens junction protein vascular endothelial (VE)-cadherin, and became leaky. This alteration was ascribed to up-regulation of angiopoetin-2 in microvascular endothelial cells. Up-regulation of the angiopoietin-2 was by TNF-α, originated from M2-like residential CD206+ macrophages, proportion of which increases as animal ages. It was concluded that antigenic burdens encountered in intestine throughout life create the condition of chronic stage of inflammation, which accumulates M2-like macrophages expressing TNF-α. The TNF-α induces vascular leakage to facilitate recruitment of immune cells into intestine under the chronic inflammatory setting. PMID:28045067

Advanced glycation end product 3 (AGE3) suppresses the mineralization of mouse stromal ST2 cells and human mesenchymal stem cells by increasing TGF-β expression and secretion.

PubMed

Notsu, Masakazu; Yamaguchi, Toru; Okazaki, Kyoko; Tanaka, Ken-ichiro; Ogawa, Noriko; Kanazawa, Ippei; Sugimoto, Toshitsugu

2014-07-01

In diabetic patients, advanced glycation end products (AGEs) cause bone fragility because of deterioration of bone quality. We previously showed that AGEs suppressed the mineralization of mouse stromal ST2 cells. TGF-β is abundant in bone, and enhancement of its signal causes bone quality deterioration. However, whether TGF-β signaling is involved in the AGE-induced suppression of mineralization during the osteoblast lineage remains unknown. We therefore examined the roles of TGF-β in the AGE-induced suppression of mineralization of ST2 cells and human mesenchymal stem cells. AGE3 significantly (P < .001) inhibited mineralization in both cell types, whereas transfection with small interfering RNA for the receptor for AGEs (RAGEs) significantly (P < .05) recovered this process in ST2 cells. AGE3 increased (P < .001) the expression of TGF-β mRNA and protein, which was partially antagonized by transfection with RAGE small interfering RNA. Treatment with a TGF-β type I receptor kinase inhibitor, SD208, recovered AGE3-induced decreases in osterix (P < .001) and osteocalcin (P < .05) and antagonized the AGE3-induced increase in Runx2 mRNA expression in ST2 cells (P < .001). Moreover, SD208 completely and dose dependently rescued AGE3-induced suppression of mineralization in both cell types. In contrast, SD208 intensified AGE3-induced suppression of cell proliferation as well as AGE3-induced apoptosis in proliferating ST2 cells. These findings indicate that, after cells become confluent, AGE3 partially inhibits the differentiation and mineralization of osteoblastic cells by binding to RAGE and increasing TGF-β expression and secretion. They also suggest that TGF-β adversely affects bone quality not only in primary osteoporosis but also in diabetes-related bone disorder.

Fisetin Reduces the Impact of Aging on Behavior and Physiology in the Rapidly Aging SAMP8 Mouse.

PubMed

Currais, Antonio; Farrokhi, Catherine; Dargusch, Richard; Armando, Aaron; Quehenberger, Oswald; Schubert, David; Maher, Pamela

2018-03-02

Alzheimer's disease (AD) is rarely addressed in the context of aging even though there is an overlap in pathology. We previously used a phenotypic screening platform based on old age-associated brain toxicities to identify the flavonol fisetin as a potential therapeutic for AD and other age-related neurodegenerative diseases. Based on earlier results with fisetin in transgenic AD mice, we hypothesized that fisetin would be effective against brain aging and cognitive dysfunction in rapidly aging senescence-accelerated prone 8 (SAMP8) mice, a model for sporadic AD and dementia. An integrative approach was used to correlate protein expression and metabolite levels in the brain with cognition. It was found that fisetin reduced cognitive deficits in old SAMP8 mice while restoring multiple markers associated with impaired synaptic function, stress, and inflammation. These results provide further evidence for the potential benefits of fisetin for the treatment of age-related neurodegenerative diseases.

Endocrine Parameters and Phenotypes of the Growth Hormone Receptor Gene Disrupted (GHR−/−) Mouse

PubMed Central

List, Edward O.; Sackmann-Sala, Lucila; Berryman, Darlene E.; Funk, Kevin; Kelder, Bruce; Gosney, Elahu S.; Okada, Shigeru; Ding, Juan; Cruz-Topete, Diana

2011-01-01

Disruption of the GH receptor (GHR) gene eliminates GH-induced intracellular signaling and, thus, its biological actions. Therefore, the GHR gene disrupted mouse (GHR−/−) has been and is a valuable tool for helping to define various parameters of GH physiology. Since its creation in 1995, this mouse strain has been used by our laboratory and others for numerous studies ranging from growth to aging. Some of the most notable discoveries are their extreme insulin sensitivity in the presence of obesity. Also, the animals have an extended lifespan, which has generated a large number of investigations into the roles of GH and IGF-I in the aging process. This review summarizes the many results derived from the GHR−/− mice. We have attempted to present the findings in the context of current knowledge regarding GH action and, where applicable, to discuss how these mice compare to GH insensitivity syndrome in humans. PMID:21123740

Age-dependent decline of nogo-a protein in the mouse cerebrum.

PubMed

Kumari, Anita; Thakur, M K

2014-11-01

Nogo-A, a myelin-associated neurite growth inhibitory protein, is implicated in synaptic plasticity. It binds to its receptor namely the Nogo-66 receptor1 (NgR1) and regulates filamentous (F) actin dynamics via small GTPases of the Rho family, RhoA kinase (ROCK), LimK and cofilin. These proteins are associated with the structural plasticity, one of the components of synaptic plasticity, which is known to decline with normal aging. So, the level of Nogo-A and its receptor NgR1 are likely to vary during normal brain aging. However, it is not clearly understood how the levels of Nogo-A and its receptor NgR1 change in the cerebrum during aging. Several studies show an age- and gender-dependent decline in synaptic plasticity. Therefore, the present study was planned to analyze the relative changes in the mRNA and protein levels of Nogo-A and NgR1 in both male and female mice cerebrum during normal aging. Western blot analysis has shown decrease in Nogo-A protein level during aging in both male and female mice cerebrum. This was further confirmed by immunofluorescence analysis. RT-PCR analysis of Nogo-A mRNA showed no significant difference in the above-mentioned groups. This was also supported by in situ hybridization. NgR1 protein and its mRNA expression levels showed no significant alteration with aging in the cerebrum of both male and female mice. Taken together, we speculate that the downregulation of Nogo-A protein might have a role in the altered synaptic plasticity during aging.

Metabolic characterization of a mouse deficient in all known leptin receptor isoforms.

PubMed

Osborn, Olivia; Sanchez-Alavez, Manuel; Brownell, Sara E; Ross, Brendon; Klaus, Joe; Dubins, Jeffrey; Beutler, Bruce; Conti, Bruno; Bartfai, Tamas

2010-01-01

We have characterized a newly generated mouse model of obesity, a mouse strain deficient in all five previously described leptin receptor isoforms. These transgenic mice, named the db (333)/db (333) mice, were identified from an ENU mutagenesis screen and carry a point mutation in the seventh exon of the db gene encoding the leptin receptor, resulting in a premature stop codon (Y(333)Stop) and gene product that lacks STAT signaling domains. db (333)/db (333) mice have a morbidly obese phenotype, with body weights diverging from wild type as early as 4 weeks of age (P < 0.05). To determine the contribution of the short isoforms of the leptin receptor in this metabolic phenotype, we performed an extensive metabolic characterization of the db (333)/db (333) mouse in relation to the well-characterized db/db mouse lacking only the long form of the leptin receptor. db (333)/db (333) mice have similar endocrine and metabolic parameters as previously described in other leptin receptor transgenic mice including db/db mice that lack only the long isoform of the leptin receptor. However, db (333)/db (333) mice show a subtle trend toward higher body weight and insulin levels, lower oxygen, carbon dioxide production, respiratory exchange ratio (RER), and temperature than db/db mice suggesting the short isoforms may play an additional role in energy homeostasis.

Targeting Th17-IL-17 Pathway in Prevention of Micro-Invasive Prostate Cancer in a Mouse Model.

PubMed

Zhang, Qiuyang; Liu, Sen; Ge, Dongxia; Cunningham, David M; Huang, Feng; Ma, Lin; Burris, Thomas P; You, Zongbing

2017-06-01

Chronic inflammation has been associated with the development and progression of human cancers including prostate cancer. The exact role of the inflammatory Th17-IL-17 pathway in prostate cancer remains unknown. In this study, we aimed to determine the importance of Th17 cells and IL-17 in a Pten-null prostate cancer mouse model. The Pten-null mice were treated by Th17 inhibitor SR1001 or anti-mouse IL-17 monoclonal antibody from 6 weeks of age up to 12 weeks of age. For SR1001 treatment, the mice were injected intraperitoneally (i.p.) twice a day with vehicle or SR1001, which was dissolved in a dimethylsulfoxide (DMSO) solution. All mice were euthanized for necropsy at 12 weeks of age. For IL-17 antibody treatment, the mice were injected intravenously (i.v.) once every two weeks with control IgG or rat anti-mouse IL-17 monoclonal antibody, which was dissolved in PBS. The injection time points were at 6, 8, and 10 weeks old. All mice were analyzed for the prostate phenotypes at 12 weeks of age. We found that either SR1001 or anti-IL-17 antibody treatment decreased the formation of micro-invasive prostate cancer in Pten-null mice. The SR1001 or anti-IL-17 antibody treated mouse prostates had reduced proliferation, increased apoptosis, and reduced angiogenesis, as well as reduced inflammatory cell infiltration. By assessing the epithelial-to-mesenchymal transition (EMT) markers, we found that SR1001 or anti-IL-17 antibody treated prostate tissues had weaker EMT phenotype compared to the control treated prostates. These results demonstrated that Th17-IL-17 pathway plays a key role in prostate cancer progression in Pten-null mice. Targeting Th17-IL-17 pathway could prevent micro-invasive prostate cancer formation in mice. Prostate 77:888-899, 2017. © 2017 Wiley Periodicals, Inc. © 2017 Wiley Periodicals, Inc.

Mouse homologues of human hereditary disease.

PubMed Central

Searle, A G; Edwards, J H; Hall, J G

1994-01-01

Details are given of 214 loci known to be associated with human hereditary disease, which have been mapped on both human and mouse chromosomes. Forty two of these have pathological variants in both species; in general the mouse variants are similar in their effects to the corresponding human ones, but exceptions include the Dmd/DMD and Hprt/HPRT mutations which cause little, if any, harm in mice. Possible reasons for phenotypic differences are discussed. In most pathological variants the gene product seems to be absent or greatly reduced in both species. The extensive data on conserved segments between human and mouse chromosomes are used to predict locations in the mouse of over 50 loci of medical interest which are mapped so far only on human chromosomes. In about 80% of these a fairly confident prediction can be made. Some likely homologies between mapped mouse loci and unmapped human ones are also given. Sixty six human and mouse proto-oncogene and growth factor gene homologies are also listed; those of confirmed location are all in known conserved segments. A survey of 18 mapped human disease loci and chromosome regions in which the manifestation or severity of pathological effects is thought to be the result of genomic imprinting shows that most of the homologous regions in the mouse are also associated with imprinting, especially those with homologues on human chromosomes 11p and 15q. Useful methods of accelerating the production of mouse models of human hereditary disease include (1) use of a supermutagen, such as ethylnitrosourea (ENU), (2) targeted mutagenesis involving ES cells, and (3) use of gene transfer techniques, with production of 'knockout mutations'. PMID:8151633

SENESCENCE (AGEING) @ 2011

PubMed Central

Nigam, Anjana

2011-01-01

Ageing, also called as senescence, is one of the most complex, intrinsic, biological processes of growing older and resulting into reduced functional ability of the organism. Telomerase, environment, low calorie diets, free radicals, etc., are all believed to affect this ageing process. A number of genetic components of ageing have been identified using model organisms. Genes, mainly the sirtuins, regulate the ageing speed by indirection and controlling organism resistance to damages by exogenous and endogenous stresses. In higher organisms, ageing is likely to be regulated, in part, through the insulin/insulin-like growth factor 1 pathway. Besides this, the induction of apoptosis in stem and progenitor cells, increased p53 activity, and autophagy is also thought to trigger premature organismal ageing. Ageing has also been shown to upregulate expression of inflammatory mediators in mouse adipose tissue. The understanding of pathophysiology of ageing over the past few years has posed tremendous challenges for the development of anti-ageing medicine for targeted therapy. Future research areas must include targeted role of systemic inflammatory markers such as C-reactive protein and interleukin 6 and other biochemical and genetic studies including gene signaling pathways, gene microarray analysis, gene modulation, gene therapy, and development of animal/human models for potential therapeutic measures and evaluations. PMID:22345758

Age-associated increase in heterochromatic marks in murine and primate tissues

PubMed Central

Kreiling, Jill A.; Tamamori-Adachi, Mimi; Sexton, Alec N.; Jeyapalan, Jessie C.; Munoz-Najar, Ursula; Peterson, Abigail L.; Manivannan, Jayameenakshi; Rogers, Elizabeth S.; Pchelintsev, Nikolay A.; Adams, Peter D.; Sedivy, John M.

2011-01-01

Summary Chromatin is highly dynamic and subject to extensive remodeling under many physiological conditions. Changes in chromatin that occur during the aging process are poorly documented and understood in higher organisms, such as mammals. We developed an immunofluorescence assay to quantitatively detect, at the single cell level, changes in the nuclear content of chromatin-associated proteins. We find increased levels of the heterochromatin-associated proteins histone macro H2A (mH2A) and heterochromatin protein 1 beta (HP1β) in human fibroblasts during replicative senescence in culture, and for the first time, an age-associated increase in these heterochromatin marks in several tissues of mice and primates. Mouse lung was characterized by monophasic mH2A expression histograms at both ages, and an increase in mean staining intensity at old age. In the mouse liver we observed increased age-associated localization of mH2A to regions of pericentromeric heterochromatin. In skeletal muscle we found two populations of cells with either low or high mH2A levels. This pattern of expression was similar in mouse and baboon, and showed a clear increase in the proportion of nuclei with high mH2A levels in older animals. The frequencies of cells displaying evidence of increased heterochromatinization are too high to be readily accounted for by replicative or oncogene-induced cellular senescence, and are prominently found in terminally differentiated, post mitotic tissues that are not conventionally thought to be susceptible to senescence. Our findings distinguish specific chromatin states in individual cells of mammalian tissues, and provide a foundation to further investigate the progressive epigenetic changes that occur during aging. PMID:21176091

Mouse Genome Informatics (MGI) Is the International Resource for Information on the Laboratory Mouse.

PubMed

Law, MeiYee; Shaw, David R

2018-01-01

Mouse Genome Informatics (MGI, http://www.informatics.jax.org/ ) web resources provide free access to meticulously curated information about the laboratory mouse. MGI's primary goal is to help researchers investigate the genetic foundations of human diseases by translating information from mouse phenotypes and disease models studies to human systems. MGI provides comprehensive phenotypes for over 50,000 mutant alleles in mice and provides experimental model descriptions for over 1500 human diseases. Curated data from scientific publications are integrated with those from high-throughput phenotyping and gene expression centers. Data are standardized using defined, hierarchical vocabularies such as the Mammalian Phenotype (MP) Ontology, Mouse Developmental Anatomy and the Gene Ontologies (GO). This chapter introduces you to Gene and Allele Detail pages and provides step-by-step instructions for simple searches and those that take advantage of the breadth of MGI data integration.

Age-associated increase in heterochromatic marks in murine and primate tissues.

PubMed

Kreiling, Jill A; Tamamori-Adachi, Mimi; Sexton, Alec N; Jeyapalan, Jessie C; Munoz-Najar, Ursula; Peterson, Abigail L; Manivannan, Jayameenakshi; Rogers, Elizabeth S; Pchelintsev, Nikolay A; Adams, Peter D; Sedivy, John M

2011-04-01

Chromatin is highly dynamic and subject to extensive remodeling under many physiologic conditions. Changes in chromatin that occur during the aging process are poorly documented and understood in higher organisms, such as mammals. We developed an immunofluorescence assay to quantitatively detect, at the single cell level, changes in the nuclear content of chromatin-associated proteins. We found increased levels of the heterochromatin-associated proteins histone macro H2A (mH2A) and heterochromatin protein 1 beta (HP1β) in human fibroblasts during replicative senescence in culture, and for the first time, an age-associated increase in these heterochromatin marks in several tissues of mice and primates. Mouse lung was characterized by monophasic mH2A expression histograms at both ages, and an increase in mean staining intensity at old age. In the mouse liver, we observed increased age-associated localization of mH2A to regions of pericentromeric heterochromatin. In the skeletal muscle, we found two populations of cells with either low or high mH2A levels. This pattern of expression was similar in mouse and baboon, and showed a clear increase in the proportion of nuclei with high mH2A levels in older animals. The frequencies of cells displaying evidence of increased heterochromatinization are too high to be readily accounted for by replicative or oncogene-induced cellular senescence, and are prominently found in terminally differentiated, postmitotic tissues that are not conventionally thought to be susceptible to senescence. Our findings distinguish specific chromatin states in individual cells of mammalian tissues, and provide a foundation to investigate further the progressive epigenetic changes that occur during aging. © 2010 The Authors. Aging Cell © 2010 Blackwell Publishing Ltd/Anatomical Society of Great Britain and Ireland.

Single-shot dimension measurements of the mouse eye using SD-OCT.

PubMed

Jiang, Minshan; Wu, Pei-Chang; Fini, M Elizabeth; Tsai, Chia-Ling; Itakura, Tatsuo; Zhang, Xiangyang; Jiao, Shuliang

2012-01-01

The authors demonstrate the feasibility and advantage of spectral-domain optical coherence tomography (SD-OCT) for single-shot ocular biometric measurement during the development of the mouse eye. A high-resolution SD-OCT system was built for single-shot imaging of the whole mouse eye in vivo. The axial resolution and imaging depth of the system are 4.5 μm (in tissue) and 5.2 mm, respectively. The system is capable of acquiring a cross-sectional OCT image consisting of 2,048 depth scans in 85 ms. The imaging capability of the SD-OCT system was validated by imaging the normal ocular growth and experimental myopia model using C57BL/6J mice. The biometric dimensions of the mouse eye can be calculated directly from one snapshot of the SD-OCT image. The biometric parameters of the mouse eye including axial length, corneal thickness, anterior chamber depth, lens thickness, vitreous chamber depth, and retinal thickness were successfully measured by the SD-OCT. In the normal ocular growth group, the axial length increased significantly from 28 to 82 days of age (P < .001). The lens thickness increased and the vitreous chamber depth decreased significantly during this period (P < .001 and P = .001, respectively). In the experimental myopia group, there were significant increases in vitreous chamber depth and axial length in comparison to the control eyes (P = .040 and P < .001, respectively). SD-OCT is capable of providing single-shot direct, fast, and high-resolution measurements of the dimensions of young and adult mouse eyes. As a result, SD-OCT is a potentially powerful tool that can be easily applied to research in eye development and myopia using small animal models. Copyright 2012, SLACK Incorporated.

Mouse hypospadias: A critical examination and definition

PubMed Central

Sinclair, Adriane Watkins; Cao, Mei; Shen, Joel; Cooke, Paul; Risbridger, Gail; Baskin, Laurence; Cunha, Gerald R.

2016-01-01

Hypospadias is a common malformation whose etiology is based upon perturbation of normal penile development. The mouse has been previously used as a model of hypospadias, despite an unacceptably wide range of definitions for this malformation. The current paper presents objective criteria and a definition of mouse hypospadias. Accordingly, diethylstilbestrol (DES) induced penile malformations were examined at 60 days postnatal (P60) in mice treated with DES over the age range of 12 days embryonic to 20 days postnatal (E12 to P20). DES-induced hypospadias involves malformation of the urethral meatus, which is most severe in DES E12-P10, DES P0-P10 and DES P5-P15 groups and less so or absent in the other treatment groups. A frenulum-like ventral tether between the penis and the prepuce was seen in the most severely affected DES-treated mice. Internal penile morphology was also altered in the DES E12-P10, DES P0-P10 and DES P5-P15 groups (with little effect in the other DES treatment groups). Thus, adverse effects of DES are a function of the period of DES treatment and most severe in the P0 to P10 period. In “estrogen mutant mice” (NERKI, βERKO, αERKO and AROM+) hypospadias was only seen in AROM+ male mice having genetically-engineered elevation is serum estrogen. Significantly, mouse hypospadias was only seen distally at and near the urethral meatus where epithelial fusion events are known to take place and never in the penile midshaft, where urethral formation occurs via an entirely different morphogenetic process. PMID:27068029

TDP-43 causes differential pathology in neuronal versus glial cells in the mouse brain

PubMed Central

Yan, Sen; Wang, Chuan-En; Wei, Wenjie; Gaertig, Marta A.; Lai, Liangxue; Li, Shihua; Li, Xiao-Jiang

2014-01-01

Mutations in TAR DNA-binding protein 43 (TDP-43) are associated with familial forms of amyotrophic lateral sclerosis and frontotemporal lobar degeneration. Although recent studies have revealed that mutant TDP-43 in neuronal and glial cells is toxic, how mutant TDP-43 causes primarily neuronal degeneration in an age-dependent manner remains unclear. Using adeno-associated virus (AAV) that expresses mutant TDP-43 (M337V) ubiquitously, we found that mutant TDP-43 accumulates preferentially in neuronal cells in the postnatal mouse brain. We then ubiquitously or selectively expressed mutant TDP-43 in neuronal and glial cells in the striatum of adult mouse brains via stereotaxic injection of AAV vectors and found that it also preferentially accumulates in neuronal cells. Expression of mutant TDP-43 in neurons in the striatum causes more severe degeneration, earlier death and more robust symptoms in mice than expression of mutant TDP-43 in glial cells; however, aging increases the expression of mutant TDP-43 in glial cells, and expression of mutant TDP-43 in older mice caused earlier onset of phenotypes and more severe neuropathology than that in younger mice. Although expression of mutant TDP-43 in glial cells via stereotaxic injection does not lead to robust neurological phenotypes, systemic inhibition of the proteasome activity via MG132 in postnatal mice could exacerbate glial TDP-43-mediated toxicity and cause mice to die earlier. Consistently, this inhibition increases the expression of mutant TDP-43 in glial cells in mouse brains. Thus, the differential accumulation of mutant TDP-43 in neuronal versus glial cells contributes to the preferential toxicity of mutant TDP-43 in neuronal cells and age-dependent pathology. PMID:24381309

TDP-43 causes differential pathology in neuronal versus glial cells in the mouse brain.

PubMed

Yan, Sen; Wang, Chuan-En; Wei, Wenjie; Gaertig, Marta A; Lai, Liangxue; Li, Shihua; Li, Xiao-Jiang

2014-05-15

Mutations in TAR DNA-binding protein 43 (TDP-43) are associated with familial forms of amyotrophic lateral sclerosis and frontotemporal lobar degeneration. Although recent studies have revealed that mutant TDP-43 in neuronal and glial cells is toxic, how mutant TDP-43 causes primarily neuronal degeneration in an age-dependent manner remains unclear. Using adeno-associated virus (AAV) that expresses mutant TDP-43 (M337V) ubiquitously, we found that mutant TDP-43 accumulates preferentially in neuronal cells in the postnatal mouse brain. We then ubiquitously or selectively expressed mutant TDP-43 in neuronal and glial cells in the striatum of adult mouse brains via stereotaxic injection of AAV vectors and found that it also preferentially accumulates in neuronal cells. Expression of mutant TDP-43 in neurons in the striatum causes more severe degeneration, earlier death and more robust symptoms in mice than expression of mutant TDP-43 in glial cells; however, aging increases the expression of mutant TDP-43 in glial cells, and expression of mutant TDP-43 in older mice caused earlier onset of phenotypes and more severe neuropathology than that in younger mice. Although expression of mutant TDP-43 in glial cells via stereotaxic injection does not lead to robust neurological phenotypes, systemic inhibition of the proteasome activity via MG132 in postnatal mice could exacerbate glial TDP-43-mediated toxicity and cause mice to die earlier. Consistently, this inhibition increases the expression of mutant TDP-43 in glial cells in mouse brains. Thus, the differential accumulation of mutant TDP-43 in neuronal versus glial cells contributes to the preferential toxicity of mutant TDP-43 in neuronal cells and age-dependent pathology.

Effect of sclerostin antibody treatment in a mouse model of severe osteogenesis imperfecta.

PubMed

Roschger, Andreas; Roschger, Paul; Keplingter, Petra; Klaushofer, Klaus; Abdullah, Sami; Kneissel, Michaela; Rauch, Frank

2014-09-01

Osteogenesis imperfecta (OI) is a heritable bone fragility disorder that is usually caused by mutations affecting collagen type I production in osteoblasts. Stimulation of bone formation through sclerostin antibody treatment (Sost-ab) has shown promising results in mouse models of relatively mild OI. We assessed the effect of once-weekly intravenous Sost-ab injections for 4weeks in male Col1a1(Jrt)/+mice, a model of severe dominant OI, starting either at 4weeks (growing mice) or at 20weeks (adult mice) of age. Sost-ab had no effect on weight or femur length. In OI mice, no significant treatment-associated differences in serum markers of bone formation (alkaline phosphatase activity, procollagen type I N-propeptide) or resorption (C-telopeptide of collagen type I) were found. Micro-CT analyses at the femur showed that Sost-ab treatment was associated with higher trabecular bone volume and higher cortical thickness in wild type mice at both ages and in growing OI mice, but not in adult OI mice. Three-point bending tests of the femur showed that in wild type but not in OI mice, Sost-ab was associated with higher ultimate load and work to failure. Quantitative backscattered electron imaging of the femur did not show any effect of Sost-ab on CaPeak (the most frequently occurring calcium concentration in the bone mineral density distribution), regardless of genotype, age or measurement location. Thus, Sost-ab had a larger effect in wild type than in Col1a1(Jrt)/+mice. Previous studies had found marked improvements of Sost-ab on bone mass and strength in an OI mouse model with a milder phenotype. Our data therefore suggest that Sost-ab is less effective in a more severely affected OI mouse model. Copyright © 2014 Elsevier Inc. All rights reserved.

Age-dependent changes of cerebral copper metabolism in Atp7b -/- knockout mouse model of Wilson's disease by [64Cu]CuCl2-PET/CT.

PubMed

Xie, Fang; Xi, Yin; Pascual, Juan M; Muzik, Otto; Peng, Fangyu

2017-06-01

Copper is a nutritional metal required for brain development and function. Wilson's disease (WD), or hepatolenticular degeneration, is an inherited human copper metabolism disorder caused by a mutation of the ATP7B gene. Many WD patients present with variable neurological and psychiatric symptoms, which may be related to neurodegeneration secondary to copper metabolism imbalance. The objective of this study was to explore the feasibility and use of copper-64 chloride ([ 64 C]CuCl 2 ) as a tracer for noninvasive assessment of age-dependent changes of cerebral copper metabolism in WD using an Atp7b -/- knockout mouse model of WD and positron emission tomography/computed tomography (PET/CT) imaging. Continuing from our recent study of biodistribution and radiation dosimetry of [ 64 C]CuCl 2 in Atp7b -/- knockout mice, PET quantitative analysis revealed low 64 Cu radioactivity in the brains of Atp7b -/- knockout mice at 7th weeks of age, compared with 64 Cu radioactivity in the brains of age- and gender-matched wild type C57BL/6 mice, at 24 h (h) post intravenous injection of [ 64 C]CuCl 2 as a tracer. Furthermore, age-dependent increase of 64 Cu radioactivity was detected in the brains of Atp7b -/- knockout mice from the 13th to 21th weeks of age, based on the data derived from a longitudinal [ 64 C]CuCl 2 -PET/CT study of Atp7b -/- knockout mice with orally administered [ 64 Cu]CuCl 2 as a tracer. The findings of this study support clinical use of [ 64 Cu]CuCl 2 -PET/CT imaging as a tool for noninvasive assessment of age-dependent changes of cerebral copper metabolism in WD patients presenting with variable neurological and psychiatric symptoms.

Erythropoiesis in the aged mouse. I. Response to stimulation in vivo

DOE Office of Scientific and Technical Information (OSTI.GOV)

Udupa, K.B.; Lipschitz, D.A.

1984-04-01

Changes in erythropoiesis with age were studied by examining the hematocrit increase in response to hypoxia in aged mice and by assessing the change in erythropoiesis following the injection of erythropoietin in young and old polycythemic mice. The increase in hematocrit after exposure to hypoxia was more variable and generally lower in old mice than in young mice. When erythropoietin was injected into polycythemic animals, the increase in differentiated erythroid cells and /sup 59/Fe incorporation into erythroid marrow and peripheral blood cells was significantly lower in old mice than in young mice. In contrast to differentiated erythroid cells, there wasmore » less evidence of a reduced response to simulation of the more primitive erythroid progenitor cells of aged animals. The early undifferentiated erythroid progenitor, burst-forming units, did not decrease when either young or aged mice were made polycythemic, and no change following erythropoietin injection was noted. Polycythemia suppressed the late-differentiated erythroid progenitor, erythroid colony-forming units, to a greater extent in aged animals, but when erythropoietin was injected, the percent increase over the subsequent 24 hours was identical to that in young mice. These observations indicate a reduced erythropoietic capacity with age, the abnormality being most obvious in the more mature erythroid precursors.« less

MR images of mouse brain using clinical 3T MR scanner and 4CH-Mouse coil

NASA Astrophysics Data System (ADS)

Lim, Soo Mee; Park, Eun Mi; Lyoo, In Kyoon; Lee, Junghyun; Han, Bo Mi; Lee, Jeong Kyong; Lee, Su Bin

2015-07-01

Objectives: Although small-bore high-field magnets are useful for research in small rodent models,this technology, however, has not been easily accessible to most researchers. This current study, thus,tried to evaluate the usability of 4CH-Mouse coil (Philips Healthcare, Best, the Netherlands) forpreclinical investigations in clinical 3T MR scan environment. We evaluated the effects of ischemicpreconditioning (IP) in the mouse stroke model with clinical 3T MR scanner and 4CH-Mouse coil. Materials and Methods: Experiments were performed on male C57BL/6 mice that either received the IP or sham operation (control). Three different MR sequences including diffusion weighted images (DWI), T2-weighted images (T2WI), and fluid attenuated inversion recovery (FLAIR) were performed on the mouse brains following 24, 72 hours of middle cerebral artery occlusion (MCAO) and analyzed for infarct lesions. Results: The images showed that the IP-treated mouse brains had significantly smaller infarct volumes compared to the control group. Of the MR sequences employed, the T2WI showed the highest level of correlations with postmortem infarct volume measurements. Conclusions: The clinical 3T MR scanner turned out to have a solid potential as a practical tool for imaging small animal brains. MR sequences including DWI, T2WI, FLAIR were obtained with acceptable resolution and in a reasonable time constraint in evaluating a mouse stroke model brain.

Premature aging and cancer in nucleotide excision repair-disorders

PubMed Central

Diderich, K.; Alanazi, M.; Hoeijmakers, J.H.J.

2014-01-01

During past decades the major impact of DNA damage on cancer as ‘disease of the genes’ has become abundantly apparent. In addition to cancer recent years have also uncovered a very strong association of DNA damage with many features of (premature) aging. The notion that DNA repair systems not only protect against cancer but equally against too fast aging has become evident from a systematic, integral analysis of a variety of mouse mutants carrying defects in e.g. transcription-coupled repair with or without an additional impairment of global genome nucleotide excision repair and the corresponding segmental premature aging syndromes in man. A striking correlation between the degree of the DNA repair deficiency and the acceleration of specific progeroid symptoms has been discovered for those repair systems that primarily protect from the cytotoxic and cytostatic effects of DNA damage. These observations are explained from the perspective of nucleotide excision repair mouse mutant and human syndromes. However, similar principles likely apply to other DNA repair pathways including interstrand crosslink repair and double strand break repair and genome maintenance systems in general, supporting the notion that DNA damage constitutes an important intermediate in the process of aging. PMID:21680258

A comparison of skin prick tests, intradermal skin tests, and specific IgE in the diagnosis of mouse allergy.

PubMed

Sharma, Hemant P; Wood, Robert A; Bravo, Andrea R; Matsui, Elizabeth C

2008-04-01

Mouse sensitization is assessed by using skin testing and serum levels of mouse allergen-specific IgE (m-IgE). However, it is unknown whether a positive skin test response or m-IgE result accurately identifies those with clinically relevant mouse sensitization. We sought to compare skin testing and m-IgE measurement in the diagnosis of mouse allergy. Sixty-nine mouse laboratory workers underwent skin prick tests (SPTs), intradermal tests (IDTs), and serum IgE measurements to mouse allergen, followed by nasal challenge to increasing concentrations of mouse allergen. Challenge response was assessed by nasal symptom score. Thirty-eight women and 31 men with a mean age of 30 years were studied. Forty-nine workers reported mouse-related symptoms, of whom 10 had positive m-IgE results and 12 had positive SPT responses. Fifteen had negative SPT responses but positive IDT responses. Positive nasal challenges were observed in 70% of workers with positive m-IgE results, 83% of workers with positive SPT responses, 33% of workers with negative SPT responses/positive IDT responses, and 0% of workers with negative IDT responses. SPTs performed best, having the highest positive and negative predictive values. Among participants with a positive challenge result, those with a positive SPT response or m-IgE result had a significantly lower challenge threshold than those with a positive IDT response (P = .01). Workers with a positive challenge result were more likely to have an increase in nasal eosinophilia after the challenge compared with those with a negative challenge result (P = .03). SPTs perform best in discriminating patients with and without mouse allergy. Mouse-specific IgE and IDTs appear to be less useful than SPTs in the diagnosis of mouse allergy.

Mouse IDGenes: a reference database for genetic interactions in the developing mouse brain

PubMed Central

Matthes, Michaela; Preusse, Martin; Zhang, Jingzhong; Schechter, Julia; Mayer, Daniela; Lentes, Bernd; Theis, Fabian; Prakash, Nilima; Wurst, Wolfgang; Trümbach, Dietrich

2014-01-01

The study of developmental processes in the mouse and other vertebrates includes the understanding of patterning along the anterior–posterior, dorsal–ventral and medial– lateral axis. Specifically, neural development is also of great clinical relevance because several human neuropsychiatric disorders such as schizophrenia, autism disorders or drug addiction and also brain malformations are thought to have neurodevelopmental origins, i.e. pathogenesis initiates during childhood and adolescence. Impacts during early neurodevelopment might also predispose to late-onset neurodegenerative disorders, such as Parkinson’s disease. The neural tube develops from its precursor tissue, the neural plate, in a patterning process that is determined by compartmentalization into morphogenetic units, the action of local signaling centers and a well-defined and locally restricted expression of genes and their interactions. While public databases provide gene expression data with spatio-temporal resolution, they usually neglect the genetic interactions that govern neural development. Here, we introduce Mouse IDGenes, a reference database for genetic interactions in the developing mouse brain. The database is highly curated and offers detailed information about gene expressions and the genetic interactions at the developing mid-/hindbrain boundary. To showcase the predictive power of interaction data, we infer new Wnt/β-catenin target genes by machine learning and validate one of them experimentally. The database is updated regularly. Moreover, it can easily be extended by the research community. Mouse IDGenes will contribute as an important resource to the research on mouse brain development, not exclusively by offering data retrieval, but also by allowing data input. Database URL: http://mouseidgenes.helmholtz-muenchen.de. PMID:25145340

Sex and gonadal hormones in mouse models of Alzheimer’s disease: what is relevant to the human condition?

PubMed Central

2012-01-01

Biologic sex and gonadal hormones matter in human aging and diseases of aging such as Alzheimer’s – and the importance of studying their influences relates directly to human health. The goal of this article is to review the literature to date on sex and hormones in mouse models of Alzheimer’s disease (AD) with an exclusive focus on interpreting the relevance of findings to the human condition. To this end, we highlight advances in AD and in sex and hormone biology, discuss what these advances mean for merging the two fields, review the current mouse model literature, raise major unresolved questions, and offer a research framework that incorporates human reproductive aging for future studies aimed at translational discoveries in this important area. Unraveling human relevant pathways in sex and hormone-based biology may ultimately pave the way to novel and urgently needed treatments for AD and other neurodegenerative diseases. PMID:23126652

Autonomic nervous system involvement in the giant axonal neuropathy (GAN) KO mouse: implications for human disease.

PubMed

Armao, Diane; Bailey, Rachel M; Bouldin, Thomas W; Kim, Yongbaek; Gray, Steven J

2016-08-01

Giant axonal neuropathy (GAN) is an inherited severe sensorimotor neuropathy. The aim of this research was to investigate the neuropathologic features and clinical autonomic nervous system (ANS) phenotype in two GAN knockout (KO) mouse models. Little is known about ANS involvement in GAN in humans, but autonomic signs and symptoms are commonly reported in early childhood. Routine histology and immunohistochemistry was performed on GAN KO mouse specimens taken at various ages. Enteric dysfunction was assessed by quantifying the frequency, weight, and water content of defecation in GAN KO mice. Histological examination of the enteric, parasympathetic and sympathetic ANS of GAN KO mice revealed pronounced and widespread neuronal perikaryal intermediate filament inclusions. These neuronal inclusions served as an easily identifiable, early marker of GAN in young GAN KO mice. Functional studies identified an age-dependent alteration in fecal weight and defecation frequency in GAN KO mice. For the first time in the GAN KO mouse model, we described the early, pronounced and widespread neuropathologic features involving the ANS. In addition, we provided evidence for a clinical autonomic phenotype in GAN KO mice, reflected in abnormal gastrointestinal function. These findings in GAN KO mice suggest that consideration should be given to ANS involvement in human GAN, especially when considering treatments and patient care.

Premature aging-related peripheral neuropathy in a mouse model of progeria.

PubMed

Goss, James R; Stolz, Donna Beer; Robinson, Andria Rasile; Zhang, Mingdi; Arbujas, Norma; Robbins, Paul D; Glorioso, Joseph C; Niedernhofer, Laura J

2011-08-01

Peripheral neuropathy is a common aging-related degenerative disorder that interferes with daily activities and leads to increased risk of falls and injury in the elderly. The etiology of most aging-related peripheral neuropathy is unknown. Inherited defects in several genome maintenance mechanisms cause tissue-specific accelerated aging, including neurodegeneration. We tested the hypothesis that a murine model of XFE progeroid syndrome, caused by reduced expression of ERCC1-XPF DNA repair endonuclease, develops peripheral neuropathy. Nerve conduction studies revealed normal nerve function in young adult (8 week) Ercc1(-/Δ) mice, but significant abnormalities in 20 week-old animals. Morphologic and ultrastructural analysis of the sciatic nerve from mutant mice revealed significant alterations at 20 but not 8 weeks of age. We conclude that Ercc1(-/Δ) mice have accelerated spontaneous peripheral neurodegeneration that mimics aging-related disease. This provides strong evidence that DNA damage can drive peripheral neuropathy and offers a rapid and novel model to test therapies. Copyright © 2011 Elsevier Ireland Ltd. All rights reserved.

Drug discovery in prostate cancer mouse models.

PubMed

Valkenburg, Kenneth C; Pienta, Kenneth J

2015-01-01

The mouse is an important, though imperfect, organism with which to model human disease and to discover and test novel drugs in a preclinical setting. Many experimental strategies have been used to discover new biological and molecular targets in the mouse, with the hopes of translating these discoveries into novel drugs to treat prostate cancer in humans. Modeling prostate cancer in the mouse, however, has been challenging, and often drugs that work in mice have failed in human trials. The authors discuss the similarities and differences between mice and men; the types of mouse models that exist to model prostate cancer; practical questions one must ask when using a mouse as a model; and potential reasons that drugs do not often translate to humans. They also discuss the current value in using mouse models for drug discovery to treat prostate cancer and what needs are still unmet in field. With proper planning and following practical guidelines by the researcher, the mouse is a powerful experimental tool. The field lacks genetically engineered metastatic models, and xenograft models do not allow for the study of the immune system during the metastatic process. There remain several important limitations to discovering and testing novel drugs in mice for eventual human use, but these can often be overcome. Overall, mouse modeling is an essential part of prostate cancer research and drug discovery. Emerging technologies and better and ever-increasing forms of communication are moving the field in a hopeful direction.

The development of behavioral abnormalities in the motor neuron degeneration (mnd) mouse.

PubMed

Bolivar, Valerie J; Scott Ganus, J; Messer, Anne

2002-05-24

The motor neuron degeneration (mnd) mouse, which has widespread abnormal accumulating lipoprotein and neuronal degeneration, has a mutation in CLN8, the gene for human progressive epilepsy with mental retardation (EPMR). EPMR is one of the neuronal ceroid lipofuscinoses (NCLs), a group of neurological disorders characterized by autofluorescent lipopigment accumulation, blindness, seizures, motor deterioration, and dementia. The human phenotype of EPMR suggests that, in addition to the motor symptoms previously categorized, various types of progressive behavioral abnormalities would be expected in mnd mice. We have therefore examined exploratory behavior, fear conditioning, and aggression in 2-3 month and 4-5 month old male mnd mice and age-matched C57BL/6 (B6) controls. The mnd mice displayed increased activity with decreased habituation in the activity monitor, poor contextual and cued memory, and heightened aggression relative to B6 controls. These behavioral deficits were most prominent at 4-5 months of age, which is prior to the onset of gross motor symptoms at 6 months. Our results provide a link from the mutation via pathology to a quantifiable multidimensional behavioral phenotype of this naturally occurring mouse model of NCL.

Chimeric elk/mouse prion proteins in transgenic mice.

PubMed

Tamgüney, Gültekin; Giles, Kurt; Oehler, Abby; Johnson, Natrina L; DeArmond, Stephen J; Prusiner, Stanley B

2013-02-01

Chronic wasting disease (CWD) of deer and elk is a highly communicable neurodegenerative disorder caused by prions. Investigations of CWD are hampered by slow bioassays in transgenic (Tg) mice. Towards the development of Tg mice that will be more susceptible to CWD prions, we created a series of chimeric elk/mouse transgenes that encode the N terminus of elk PrP (ElkPrP) up to residue Y168 and the C terminus of mouse PrP (MoPrP) beyond residue 169 (mouse numbering), designated Elk3M(SNIVVK). Between codons 169 and 219, six residues distinguish ElkPrP from MoPrP: N169S, T173N, V183I, I202V, I214V and R219K. Using chimeric elk/mouse PrP constructs, we generated 12 Tg mouse lines and determined incubation times after intracerebral inoculation with the mouse-passaged RML scrapie or Elk1P CWD prions. Unexpectedly, one Tg mouse line expressing Elk3M(SNIVVK) exhibited incubation times of <70 days when inoculated with RML prions; a second line had incubation times of <90 days. In contrast, mice expressing full-length ElkPrP had incubation periods of >250 days for RML prions. Tg(Elk3M,SNIVVK) mice were less susceptible to CWD prions than Tg(ElkPrP) mice. Changing three C-terminal mouse residues (202, 214 and 219) to those of elk doubled the incubation time for mouse RML prions and rendered the mice resistant to Elk1P CWD prions. Mutating an additional two residues from mouse to elk at codons 169 and 173 increased the incubation times for mouse prions to >300 days, but made the mice susceptible to CWD prions. Our findings highlight the role of C-terminal residues in PrP that control the susceptibility and replication of prions.

β-Cell Ca(2+) dynamics and function are compromised in aging.

PubMed

Barker, Christopher J; Li, Luosheng; Köhler, Martin; Berggren, Per-Olof

2015-01-01

Defects in pancreatic β-cell function and survival are key components in type 2 diabetes (T2D). An age-dependent deterioration in β-cell function has also been observed, but little is known about the molecular mechanisms behind this phenomenon. Our previous studies indicate that the regulation of cytoplasmic free Ca(2+) concentration ([Ca(2+)]i) may be critical and that this is dependent on the proper function of the mitochondria. The [Ca(2+)]i dynamics of the pancreatic β-cell are driven by an interplay between glucose-induced influx of extracellular Ca(2+) via voltage-dependent Ca(2+) channels and the inositol 1,4,5-trisphosphate (Ins(1,4,5)P3)-mediated liberation of Ca(2+) from intracellular stores. Our previous work has indicated a direct relationship between disruption of Ins(1,4,5)P3-mediated Ca(2+) regulation and loss of β-cell function, including disturbed [Ca(2+)]i dynamics and compromised insulin secretion. To investigate these processes in aging we used three mouse models, a premature aging mitochondrial mutator mouse, a mature aging phenotype (C57BL/6) and an aging-resistant phenotype (129). Our data suggest that age-dependent impairment in mitochondrial function leads to modest changes in [Ca(2+)]i dynamics in mouse β-cells, particularly in the pattern of [Ca(2+)]i oscillations. These changes are driven by modifications in both PLC/Ins(1,4,5)P3-mediated Ca(2+) mobilization from intracellular stores and decreased β-cell Ca(2+) influx over the plasma membrane. Our findings underscore an important concept, namely that even relatively small, time-dependent changes in β-cell signal-transduction result in compromised insulin release and in a diabetic phenotype. Copyright © 2014 Elsevier Ltd. All rights reserved.

Evaluating Health Span in Preclinical Models of Aging and Disease: Guidelines, Challenges, and Opportunities for Geroscience

PubMed Central

Huffman, Derek M.; Justice, Jamie N.; Stout, Michael B.; Kirkland, James L.; Barzilai, Nir

2016-01-01

Life extension is no longer considered sufficient evidence of delayed aging in research animals. It must also be demonstrated that a broad swathe of health indicators have been extended. During a retreat of the Geroscience Network, a consortium of basic and clinical aging researchers, potential measures of mouse health were considered for their potential as easily standardized, highly informative metrics. Major health domains considered were neuromuscular, cognitive, cardiovascular, metabolic, and inflammatory functions as well as body composition and energetics and a multitude of assays interrogating these domains. A particularly sensitive metric of health is the ability to respond to, and recover, from stress. Therefore, the Network also considered stresses of human relevance that could be implemented in mouse models to assess frailty and resilience. Mouse models already exist for responses to forced immobility, cancer chemotherapy, infectious diseases, dietary challenges, and surgical stress, and it was felt that these could be employed to determine whether putative senescence-retarding interventions increased and extended organismal robustness. The Network discussed challenges in modeling age-related human chronic diseases and concluded that more attention needs to be paid to developing disease models with later age of onset, models of co- and multimorbidity, diversifying the strains and sexes commonly used in aging research, and considering additional species. PMID:27535967

A New Preclinical Paradigm for Testing Anti-Aging Therapeutics.

PubMed

Ladiges, Warren; Snyder, Jessica M; Wilkinson, Erby; Imai, Denise M; Snider, Tim; Ge, Xuan; Ciol, Marcia; Pettan-Brewer, Christina; Pillai, Smitha P S; Morton, John; Quarles, Ellen; Rabinovitch, Peter; Niedernhofer, Laura; Liggitt, Denny

2017-06-01

Testing drugs for anti-aging effects has historically been conducted in mouse life-span studies, but are costly and time consuming, and more importantly, difficult to recapitulate in humans. In addition, life-span studies in mice are not well suited to testing drug combinations that target multiple factors involved in aging. Additional paradigms for testing therapeutics aimed at slowing aging are needed. A new paradigm, designated as the Geropathology Grading Platform (GGP), is based on a standardized set of guidelines developed to detect the presence or absence of low-impact histopathological lesions and to determine the level of severity of high-impact lesions in organs from aged mice. The GGP generates a numerical score for each age-related lesion in an organ, summed for total lesions, and averaged over multiple mice to obtain a composite lesion score (CLS). Preliminary studies show that the platform generates CLSs that increase with the age of mice in an organ-dependent manner. The CLSs are sensitive enough to detect changes elicited by interventions that extend mouse life span, and thus help validate the GGP as a novel tool to measure biological aging. While currently optimized for mice, the GGP could be adapted to any preclinical animal model. © The Author 2017. Published by Oxford University Press on behalf of The Gerontological Society of America. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

9 CFR 113.33 - Mouse safety tests.

Code of Federal Regulations, 2010 CFR

2010-01-01

... 9 Animals and Animal Products 1 2010-01-01 2010-01-01 false Mouse safety tests. 113.33 Section 113... Procedures § 113.33 Mouse safety tests. One of the mouse safety tests provided in this section shall be... or more ingredients makes the biological product lethal or toxic for mice but not lethal or toxic for...

9 CFR 113.33 - Mouse safety tests.

Code of Federal Regulations, 2011 CFR

2011-01-01

... 9 Animals and Animal Products 1 2011-01-01 2011-01-01 false Mouse safety tests. 113.33 Section 113... Procedures § 113.33 Mouse safety tests. One of the mouse safety tests provided in this section shall be... or more ingredients makes the biological product lethal or toxic for mice but not lethal or toxic for...

9 CFR 113.33 - Mouse safety tests.

Code of Federal Regulations, 2013 CFR

2013-01-01

... 9 Animals and Animal Products 1 2013-01-01 2013-01-01 false Mouse safety tests. 113.33 Section 113... Procedures § 113.33 Mouse safety tests. One of the mouse safety tests provided in this section shall be... or more ingredients makes the biological product lethal or toxic for mice but not lethal or toxic for...

9 CFR 113.33 - Mouse safety tests.

Code of Federal Regulations, 2012 CFR

2012-01-01

... 9 Animals and Animal Products 1 2012-01-01 2012-01-01 false Mouse safety tests. 113.33 Section 113... Procedures § 113.33 Mouse safety tests. One of the mouse safety tests provided in this section shall be... or more ingredients makes the biological product lethal or toxic for mice but not lethal or toxic for...

9 CFR 113.33 - Mouse safety tests.

Code of Federal Regulations, 2014 CFR

2014-01-01

... 9 Animals and Animal Products 1 2014-01-01 2014-01-01 false Mouse safety tests. 113.33 Section 113... Procedures § 113.33 Mouse safety tests. One of the mouse safety tests provided in this section shall be... or more ingredients makes the biological product lethal or toxic for mice but not lethal or toxic for...

Mouse IDGenes: a reference database for genetic interactions in the developing mouse brain.

PubMed

Matthes, Michaela; Preusse, Martin; Zhang, Jingzhong; Schechter, Julia; Mayer, Daniela; Lentes, Bernd; Theis, Fabian; Prakash, Nilima; Wurst, Wolfgang; Trümbach, Dietrich

2014-01-01

The study of developmental processes in the mouse and other vertebrates includes the understanding of patterning along the anterior-posterior, dorsal-ventral and medial- lateral axis. Specifically, neural development is also of great clinical relevance because several human neuropsychiatric disorders such as schizophrenia, autism disorders or drug addiction and also brain malformations are thought to have neurodevelopmental origins, i.e. pathogenesis initiates during childhood and adolescence. Impacts during early neurodevelopment might also predispose to late-onset neurodegenerative disorders, such as Parkinson's disease. The neural tube develops from its precursor tissue, the neural plate, in a patterning process that is determined by compartmentalization into morphogenetic units, the action of local signaling centers and a well-defined and locally restricted expression of genes and their interactions. While public databases provide gene expression data with spatio-temporal resolution, they usually neglect the genetic interactions that govern neural development. Here, we introduce Mouse IDGenes, a reference database for genetic interactions in the developing mouse brain. The database is highly curated and offers detailed information about gene expressions and the genetic interactions at the developing mid-/hindbrain boundary. To showcase the predictive power of interaction data, we infer new Wnt/β-catenin target genes by machine learning and validate one of them experimentally. The database is updated regularly. Moreover, it can easily be extended by the research community. Mouse IDGenes will contribute as an important resource to the research on mouse brain development, not exclusively by offering data retrieval, but also by allowing data input. http://mouseidgenes.helmholtz-muenchen.de. © The Author(s) 2014. Published by Oxford University Press.

Obesity in aging exacerbates blood-brain barrier disruption, neuroinflammation, and oxidative stress in the mouse hippocampus: effects on expression of genes involved in beta-amyloid generation and Alzheimer's disease.

PubMed

Tucsek, Zsuzsanna; Toth, Peter; Sosnowska, Danuta; Gautam, Tripti; Mitschelen, Matthew; Koller, Akos; Szalai, Gabor; Sonntag, William E; Ungvari, Zoltan; Csiszar, Anna

2014-10-01

There is growing evidence that obesity has deleterious effects on the brain and cognitive function in the elderly population. However, the specific mechanisms through which aging and obesity interact to promote cognitive decline remain unclear. To test the hypothesis that aging exacerbates obesity-induced cerebromicrovascular damage and neuroinflammation, we compared young (7 months) and aged (24 months) high fat diet-fed obese C57BL/6 mice. Aging exacerbated obesity-induced systemic inflammation and blood-brain barrier disruption, as indicated by the increased circulating levels of proinflammatory cytokines and increased presence of extravasated immunoglobulin G in the hippocampus, respectively. Obesity-induced blood-brain barrier damage was associated with microglia activation, upregulation of activating Fc-gamma receptors and proinflammatory cytokines, and increased oxidative stress. Treatment of cultured primary microglia with sera derived from aged obese mice resulted in significantly more pronounced microglia activation and oxidative stress, as compared with treatment with young sera. Serum-induced activation and oxidative stress were also exacerbated in primary microglia derived from aged animals. Hippocampal expression of genes involved in regulation of the cellular amyloid precursor protein-dependent signaling pathways, beta-amyloid generation, and the pathogenesis of tauopathy were largely unaffected by obesity in aged mice. Collectively, obesity in aging is associated with a heightened state of systemic inflammation, which exacerbates blood-brain barrier disruption. The resulting neuroinflammation and oxidative stress in the mouse hippocampus likely contribute to the significant cognitive decline observed in aged obese animals. © The Author 2013. Published by Oxford University Press on behalf of The Gerontological Society of America. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

The Virtual Mouse Brain: A Computational Neuroinformatics Platform to Study Whole Mouse Brain Dynamics.

PubMed

Melozzi, Francesca; Woodman, Marmaduke M; Jirsa, Viktor K; Bernard, Christophe

2017-01-01

Connectome-based modeling of large-scale brain network dynamics enables causal in silico interrogation of the brain's structure-function relationship, necessitating the close integration of diverse neuroinformatics fields. Here we extend the open-source simulation software The Virtual Brain (TVB) to whole mouse brain network modeling based on individual diffusion magnetic resonance imaging (dMRI)-based or tracer-based detailed mouse connectomes. We provide practical examples on how to use The Virtual Mouse Brain (TVMB) to simulate brain activity, such as seizure propagation and the switching behavior of the resting state dynamics in health and disease. TVMB enables theoretically driven experimental planning and ways to test predictions in the numerous strains of mice available to study brain function in normal and pathological conditions.

Mitochondrial proteomic profiling reveals increased carbonic anhydrase II in aging and neurodegeneration.

PubMed

Pollard, Amelia; Shephard, Freya; Freed, James; Liddell, Susan; Chakrabarti, Lisa

2016-10-10

Carbonic anhydrase inhibitors are used to treat glaucoma and cancers. Carbonic anhydrases perform a crucial role in the conversion of carbon dioxide and water into bicarbonate and protons. However, there is little information about carbonic anhydrase isoforms during the process of ageing. Mitochondrial dysfunction is implicit in ageing brain and muscle. We have interrogated isolated mitochondrial fractions from young adult and middle aged mouse brain and skeletal muscle. We find an increase of tissue specific carbonic anhydrases in mitochondria from middle-aged brain and skeletal muscle. Mitochondrial carbonic anhydrase II was measured in the Purkinje cell degeneration ( pcd 5J ) mouse model. In pcd 5J we find mitochondrial carbonic anhydrase II is also elevated in brain from young adults undergoing a process of neurodegeneration. We show C.elegans exposed to carbonic anhydrase II have a dose related shorter lifespan suggesting that high CAII levels are in themselves life limiting. We show for the first time that the mitochondrial content of brain and skeletal tissue are exposed to significantly higher levels of active carbonic anhydrases as early as in middle-age. Carbonic anhydrases associated with mitochondria could be targeted to specifically modulate age related impairments and disease.

Mouse hypospadias: A critical examination and definition.

PubMed

Sinclair, Adriane Watkins; Cao, Mei; Shen, Joel; Cooke, Paul; Risbridger, Gail; Baskin, Laurence; Cunha, Gerald R

2016-12-01

Hypospadias is a common malformation whose etiology is based upon perturbation of normal penile development. The mouse has been previously used as a model of hypospadias, despite an unacceptably wide range of definitions for this malformation. The current paper presents objective criteria and a definition of mouse hypospadias. Accordingly, diethylstilbestrol (DES) induced penile malformations were examined at 60 days postnatal (P60) in mice treated with DES over the age range of 12 days embryonic to 20 days postnatal (E12-P20). DES-induced hypospadias involves malformation of the urethral meatus, which is most severe in DES E12-P10, DES P0-P10 and DES P5-P15 groups, and less so or absent in the other treatment groups. A frenulum-like ventral tether between the penis and the prepuce was seen in the most severely affected DES-treated mice. Internal penile morphology was also altered in the DES E12-P10, DES P0-P10 and DES P5-P15 groups (with little effect in the other DES treatment groups). Thus, adverse effects of DES are a function of the period of DES treatment and most severe in the P0-P10 period. In "estrogen mutant mice" (NERKI, βERKO, αERKO and AROM+) hypospadias was only seen in AROM+ male mice having genetically-engineered elevation is serum estrogen. Significantly, mouse hypospadias was only seen distally at and near the urethral meatus where epithelial fusion events are known to take place and never in the penile midshaft, where urethral formation occurs via an entirely different morphogenetic process. Copyright © 2016 International Society of Differentiation. Published by Elsevier B.V. All rights reserved.

Corneal Expression of SLURP-1 by Age, Sex, Genetic Strain, and Ocular Surface Health

PubMed Central

Swamynathan, Sudha; Delp, Emili E.; Harvey, Stephen A. K.; Loughner, Chelsea L.; Raju, Leela; Swamynathan, Shivalingappa K.

2015-01-01

Purpose Although secreted Ly6/urokinase-type plasminogen activator receptor–related protein-1 (Slurp1) transcript is highly abundant in the mouse cornea, corresponding protein expression remains uncharacterized. Also, SLURP1 was undetected in previous tear proteomics studies, resulting in ambiguity about its baseline levels. Here, we examine mouse corneal Slurp1 expression in different sexes, age groups, strains, and health conditions, and quantify SLURP1 in human tears from healthy or inflamed ocular surfaces. Methods Expression of Slurp1 in embryonic day-13 (E13), E16, postnatal day-1 (PN1), PN10, PN20, and PN70 Balb/C, FVBN, C57Bl/6, and DBA/2J mouse corneas, Klf4Δ/ΔCE corneas with corneal epithelial–specific ablation of Klf4, migrating cells in wild-type corneal epithelial wound edge, and in corneas exposed to pathogen-associated molecular patterns (PAMPs) poly(I:C), zymosan-A, or Pam3Csk4 was examined by QPCR, immunoblots, and immunofluorescent staining. Human SLURP1 levels were quantified by ELISA in tears from 34 men and women aged 18 to 80 years. Results Expression of Slurp1, comparable in different strains and sexes, was low in E13, E16, PN1, and PN10 mouse corneas, and increased rapidly after eyelid opening in a Klf4-dependent manner. We found Slurp1 was downregulated in corneas exposed to PAMPs, and in migrating cells at the wound edge. Human SLURP1 expression, comparable in different sexes and age groups, was significantly decreased in tears from inflamed ocular surfaces (0.34%) than those from healthy individuals (0.77%). Conclusions These data describe the influence of age, sex, genetic background, and ocular surface health on mouse corneal expression of Slurp1, establish the baseline for human tear SLURP1 expression, and identify SLURP1 as a useful diagnostic and/or therapeutic target for inflammatory ocular surface disorders. PMID:26670825

Folate supplementation differently affects uracil content in DNA in the mouse colon and liver

USDA-ARS?s Scientific Manuscript database

High folate intake may increase the risk of cancer, especially in the elderly. The present study examined the effects of ageing and dietary folate on uracil misincorporation into DNA, which has a mutagenic effect, in the mouse colon and liver. Old (18 months; n 42) and young (4 months; n 42) male C5...

How Mouse-tracking Can Advance Social Cognitive Theory.

PubMed

Stillman, Paul E; Shen, Xi; Ferguson, Melissa J

2018-06-01

Mouse-tracking - measuring computer-mouse movements made by participants while they choose between response options - is an emerging tool that offers an accessible, data-rich, and real-time window into how people categorize and make decisions. In the present article we review recent research in social cognition that uses mouse-tracking to test models and advance theory. In particular, mouse-tracking allows examination of nuanced predictions about both the nature of conflict (e.g., its antecedents and consequences) as well as how this conflict is resolved (e.g., how decisions evolve). We demonstrate how mouse-tracking can further our theoretical understanding by highlighting research in two domains - social categorization and self-control. We conclude with future directions and a discussion of the limitations of mouse-tracking as a method. Copyright © 2018 Elsevier Ltd. All rights reserved.

Effects of environmental enrichment on the amyotrophic lateral sclerosis mouse model.

PubMed

Sorrells, A D; Corcoran-Gomez, K; Eckert, K A; Fahey, A G; Hoots, B L; Charleston, L B; Charleston, J S; Roberts, C R; Markowitz, H

2009-04-01

The manner in which an animal's environment is furnished may have significant implications for animal welfare as well as research outcomes. We evaluated four different housing conditions to determine the effects of what has been considered standard rodent enrichment and the exercise opportunities those environments allow on disease progression in the amyotrophic lateral sclerosis mouse model. Forty-eight copper/zinc superoxide dismutase mice (strain: B6SJL-TgN [SOD1-G931]1Gur) (SOD1) and 48 control (C) (strain: B6SJL-TgN[SOD1]2Gur) male mice were randomly assigned to four different conditions where 12 SOD1 and 12 C animals were allotted to each condition (n = 96). Conditions tested the effects of standard housing, a forced exercise regime, access to a mouse house and opportunity for ad libitum exercise on a running wheel. In addition to the daily all-occurrence behavioural sampling, mice were weighed and tested twice per week on gait and Rotor-Rod performance until the mice reached the age of 150 days (C) or met the criteria for our humane endpoint (SOD1). The SOD1 mice exposed to the forced exercise regime and wheel access did better in average lifespan and Rotor-Rod performance, than SOD1 mice exposed to the standard cage and mouse house conditions. In SOD1 mice, stride length remained longest throughout the progression of the disease in mice exposed to the forced exercise regime compared with other SOD1 conditions. Within the control group, mice in the standard cage and forced exercise regime conditions performed significantly less than the mice with the mouse house and wheels on the Rotor-Rod. Alpha motor neuron counts were highest in mice with wheels and in mice exposed to forced exercise regime in both mouse strains. All SOD1 mice had significantly lower alpha neuron counts than controls (P < 0.05). These data show that different enrichment strategies affect behaviour and disease progression in a transgenic mouse model, and may have implications for the

Effects of the activin A-myostatin-follistatin system on aging bone and muscle progenitor cells

PubMed Central

Bowser, Matthew; Herberg, Samuel; Arounleut, Phonepasong; Shi, Xingming; Fulzele, Sadanand; Hill, William D.; Isales, Carlos M.; Hamrick, Mark W.

2013-01-01

The activin A-myostatin-follistatin system is thought to play an important role in the regulation of muscle and bone mass throughout growth, development, and aging; however, the effects of these ligands on progenitor cell proliferation and differentiation in muscle and bone are not well understood. In addition, age-associated changes in the relative expression of these factors in musculoskeletal tissues have not been described. We therefore examined changes in protein levels of activin A, follistatin, and myostatin (GDF-8) in both muscle and bone with age in C57BL6 mice using ELISA. We then investigated the effects of activin A, myostatin and follistatin on the proliferation and differentiation of primary myoblasts and mouse bone marrow stromal cells (BMSCs) in vitro. Myostatin levels and the myostatin:follistatin ratio increased with age in the primarily slow-twitch mouse soleus muscle, whereas the pattern was reversed with age in the fast-twitch extensor digitorum longus muscle. Myostatin levels and the myostatin: follistatin ratio increased significantly (+75%) in mouse bone marrow with age, as did activin A levels (+17%). Follistatin increased the proliferation of primary myoblasts from both young and aged mice, whereas myostatin increased proliferation of younger myoblasts but decreased proliferation of older myoblasts. Myostatin reduced proliferation of both young and aged BMSCs in a dose-dependent fashion, and activin A increased mineralization in both young and aged BMSCs. Together these data suggest that aging in mice is accompanied by changes in the expression of activin A and myostatin, as well as changes in the response of bone and muscle progenitor cells to these factors. Myostatin appears to play a particularly important role in the impaired proliferative capacity of muscle and bone progenitor cells from aged mice. PMID:23178301

Surface immunoglobulin on cultured foetal mouse thymocytes

PubMed Central

Haustein, D.; Mandel, T. E.

1979-01-01

Organ cultures of 14–15 day foetal mouse thymus were used as a source of non-neoplastic differentiating T cells, free of contaminating B cells. Viable cells obtained from such cultured thymuses were radio-iodinated and immunoglobulins (Ig) were isolated by co-precipitation from the 125I-labelled cell-surface proteins released during 1 h of incubation at 37°. The precipitates, both reduced and unreduced, were then analysed by polyacrylamide gel electrophoresis. The unreduced material migrated in a 5% gel as a single peak with a mobility slightly faster than that of mouse IgG. After reduction, however, two peaks were obtained (in a 10% gel), one corresponding in migration to mouse light chain and the other which moved slightly faster than mouse μ chain. This pattern was identical with that previously seen for both surface Ig of normal mouse thymocytes and neoplastic T lymphoma cells. Uncultured, 15 day foetal thymocytes did not produce any detectable co-precipitated cell surface material. Ig detected in these experiments was therefore produced during in vitro culture by non-neoplastic T cells in a system free of contaminating B cells and mouse serum proteins. PMID:315364

Muro-Neuro-Urodynamics; a Review of the Functional Assessment of Mouse Lower Urinary Tract Function.

PubMed

Ito, Hiroki; Pickering, Anthony E; Igawa, Yasuhiko; Kanai, Anthony J; Fry, Christopher H; Drake, Marcus J