bluuebunny/crossref_metadata_2025 huggingface dataset:
Protecting wildlife from predation by owned domestic cats: Application of a precautionary approach to the acceptability of proposed cat regulations
Authors: LILITH MAGGIE , CALVER MICHAEL , STYLES IRENE , GARKAKLIS MARK
Published: March 2006

Abstract While it is undeniable that owned domestic catsFelis catus(Mammalia: Felidae) kill large numbers of wildlife, it is contentious if this has significant impacts on wildlife populations. Under the precautionary principle such uncertainty does not preclude measures to reduce putative risk, but action should follow consultation with stakeholders. To initiate such consultation for the City of Armadale, Western Australia, we surveyed urban and rural residents to determine their opinions regarding putative impacts of owned cats on wildlife and the acceptability of proposed regulations. Key statements accepted by 70% or more of respondents, irrespective of their residence, gender or cat ownership status, included: (i) there is a need to regulate owned domestic cats; (ii) the presence of cats in nature reserves is harmful to wildlife; (iii) cats not owned by licensed breeders should be desexed; and (iv) local councils should be empowered to restrict the maximum number of cats per household. Seventy per cent or more of owners agreed to keep their cats on their property from sunset to sunrise and to register them if these measures became compulsory. All groups except urban men also indicated 70% or greater willingness to keep their cats on their property constantly if required. However, fewer than 40% of owners supported empowering local councils to enforce cat‐free zones. In this community, cat regulation excluding cat‐free zones should enjoy support. Similar approaches should be effective wherever the environmental impacts of owned domestic cats are debated, because compliance with such regulations should be high.
Species interactions and habitat associations of birds inhabiting urban areas of Sydney, Australia
Authors: PARSONS HOLLY , MAJOR RICHARD E. , FRENCH KRIS
Published: March 2006

Abstract  The absence of small birds from many suburban areas may be due to adverse garden characteristics, interspecific aggression or human behaviour such as supplementary food provisioning that encourages predators. We investigated the relationship between these factors and the presence of seven small bird species in Sydney through a community‐based survey. The survey was conducted by participants over a 7‐day period between 7 am and 10 am in November and early December 2000. Three dominant species, the noisy miner (Manorina melanocephala), pied currawong (Strepera graculina) and common myna (Acridotheres tristis) were each present in over 59% of gardens. Each small bird species was present in less than 40% of gardens. All small birds were negatively associated with noisy miners, but only the silvereye (Zosterops lateralis) was negatively associated with pied currawongs. None of the species of small birds was negatively associated with common mynas. Four species of small birds were associated with at least one habitat variable, notably the proportion of native vegetation. Although more birds were recorded in gardens in which meat was provided, there were significantly fewer small birds in these gardens. There were also more birds recorded in gardens where seed was provided, with red‐browed finches (Neochmia temporalis) positively associated with seed provisioning in most regions of Sydney. The presence of dogs and cats was not related to the total abundance of birds overall or small birds in gardens. While garden characteristics may influence the presence of small birds to some degree, the presence of noisy miners, a species that are thought to aggressively exclude other species from their territories, is likely to be an important influence on these species in suburban areas. Furthermore, supplementary feeding by people is likely to negatively influence some small birds. The presence of carnivorous pets does not seem to influence the presence of small birds at the scale of the individual garden.
Seasonality and the dynamics of infectious diseases
Authors: Altizer Sonia , Dobson Andrew , Hosseini Parviez , Hudson Peter , Pascual Mercedes , Rohani Pejman
Published: March 2006

Seasonal variations in temperature, rainfall and resource availability are ubiquitous and can exert strong pressures on population dynamics. Infectious diseases provide some of the best‐studied examples of the role of seasonality in shaping population fluctuations. In this paper, we review examples from human and wildlife disease systems to illustrate the challenges inherent in understanding the mechanisms and impacts of seasonal environmental drivers. Empirical evidence points to several biologically distinct mechanisms by which seasonality can impact host–pathogen interactions, including seasonal changes in host social behaviour and contact rates, variation in encounters with infective stages in the environment, annual pulses of host births and deaths and changes in host immune defences. Mathematical models and field observations show that the strength and mechanisms of seasonality can alter the spread and persistence of infectious diseases, and that population‐level responses can range from simple annual cycles to more complex multiyear fluctuations. From an applied perspective, understanding the timing and causes of seasonality offers important insights into how parasite–host systems operate, how and when parasite control measures should be applied, and how disease risks will respond to anthropogenic climate change and altered patterns of seasonality. Finally, by focusing on well‐studied examples of infectious diseases, we hope to highlight general insights that are relevant to other ecological interactions.
Annual cycles of solar insolation predict spawning times of Caribbean corals
Authors: Van Woesik R. , Lacharmoise F. , Köksal S.
Published: March 2006

Seasonal increases in sea surface temperature (SST) have long been considered the trigger for mass spawning events in reef corals. We critically examined the relationship between SST and the spawning activity of broadcasting corals in the tropical western Atlantic (Caribbean). This meta‐analysis examined 12 species of broadcasting corals at 25 sites spanning 22 degrees of latitude (10°–32° N) from Venezuela to Bermuda in the Atlantic Ocean from 1986 to 2004. Sigmoidal logit regression models were used to examine the relationship between the release of reef‐coral gametes and the environmental variables SST and solar insolation defined as (1) the cumulative response 7–10 months prior to spawning (integral); (2) the rate of change at the time of spawning (derivative); and (3) the average for the month of spawning. The Quasi–Newton method was used to estimate the maximum likelihood of the response function. We demonstrate that the recent history and rate of change in temperature correlate poorly with the timing of spawning, while the average temperature during the month of spawning was significant (with all corals releasing gametes 28–30 °C, except Montastraea annularis, which released gametes at 27–30 °C). In contrast, the rate of change and the cumulative response of solar insolation cycles was a better predictor of gamete release, but solar insolation intensity at the time of spawning was not. These models have important implications for predicting coral reproductive cycles in all oceans, and for examining other marine phototrophic systems beyond corals.
Early onset of secondary extinctions in ecological communities following the loss of top predators
Authors: Borrvall Charlotte , Ebenman Bo
Published: March 2006

The large vulnerability of top predators to human‐induced disturbances on ecosystems is a matter of growing concern. Because top predators often exert strong influence on their prey populations their extinction can have far‐reaching consequences for the structure and functioning of ecosystems. It has, for example, been observed that the local loss of a predator can trigger a cascade of secondary extinctions. However, the time lags involved in such secondary extinctions remain unexplored. Here we show that the loss of a top predator leads to a significantly earlier onset of secondary extinctions in model communities than does the loss of a species from other trophic levels. Moreover, in most cases time to secondary extinction increases with increasing species richness. If local secondary extinctions occur early they are less likely to be balanced by immigration of species from local communities nearby. The implications of these results for community persistence and conservation priorities are discussed.
Testing the role of parasites in driving the cyclic population dynamics of a gamebird
Authors: Redpath Stephen M. , Mougeot François , Leckie Fiona M. , Elston David A. , Hudson Peter J.
Published: March 2006

The role of parasites in regulating populations has been the subject of debate. We tested whether parasites caused population cycles in red grouse by manipulating parasite intensities in four, paired 1 km2 study areas during cyclic population declines over 4 years. Parasite reductions led to (1) larger grouse broods, (2) higher population densities in both autumn and spring, (3) reduced autumn population declines in one of two regions, and (4) reduced spring declines, but only in the first year. We infer that a single trophic interaction between a parasite and its host does not explain cyclic dynamics in spring breeding density in this species, although it contributed to the start of a cyclic decline. Another process was operating to drive the populations down. Together with our other results these findings emphasize that both trophic and intrinsic processes may act within populations to cause unstable dynamics.
Biological control agents elevate hantavirus by subsidizing deer mouse populations
Authors: Pearson Dean E. , Callaway Ragan M.
Published: March 2006

Biological control of exotic invasive plants using exotic insects is practiced under the assumption that biological control agents are safe if they do not directly attack non‐target species. We tested this assumption by evaluating the potential for two host‐specific biological control agents (Urophora spp.), widely established in North America for spotted knapweed (Centaurea maculosa) control, to indirectly elevate Sin Nombre hantavirus by providing food subsidies to populations of deer mice (Peromyscus maniculatus), the primary reservoir for the virus. We show that seropositive deer mice (mice testing positive for hantavirus) were over three times more abundant in the presence of the biocontrol food subsidy. Elevating densities of seropositive mice may increase risk of hantavirus infection in humans and significantly alter hantavirus ecology. Host specificity alone does not ensure safe biological control. To minimize indirect risks to non‐target species, biological control agents must suppress pest populations enough to reduce their own numbers.
Likelihood Inference for a Class of Latent Markov Models under Linear Hypotheses on the Transition Probabilities
Authors: Bartolucci Francesco
Published: March 2006

For a class of latent Markov models for discrete variables having a longitudinal structure, we introduce an approach for formulating and testing linear hypotheses on the transition probabilities of the latent process. For the maximum likelihood estimation of a latent Markov model under hypotheses of this type, we outline an EM algorithm that is based on well-known recursions in the hidden Markov literature. We also show that, under certain assumptions, the asymptotic null distribution of the likelihood ratio statistic for testing a linear hypothesis on the transition probabilities of a latent Markov model, against a less stringent linear hypothesis on the transition probabilities of the same model, is of χ¯2 type. As a particular case, we derive the asymptotic distribution of the likelihood ratio statistic between a latent class model and its latent Markov version, which may be used to test the hypothesis of absence of transition between latent states. The approach is illustrated through a series of simulations and two applications, the first of which is based on educational testing data that have been collected within the National Assessment of Educational Progress 1996, and the second on data, concerning the use of marijuana, which have been collected within the National Youth Survey 1976–1980.
Mean-Squared Error Estimation in Transformed Fay–Herriot Models
Authors: Slud Eric V. , Maiti Tapabrata
Published: March 2006

The problem of accurately estimating the mean-squared error of small area estimators within a Fay–Herriot normal error model is studied theoretically in the common setting where the model is fitted to a logarithmically transformed response variable. For bias-corrected empirical best linear unbiased predictor small area point estimators, mean-squared error formulae and estimators are provided, with biases of smaller order than the reciprocal of the number of small areas. The performance of these mean-squared error estimators is illustrated by a simulation study and a real data example relating to the county level estimation of child poverty rates in the US Census Bureau's on-going ‘Small area income and poverty estimation’ project.
Sustaining critically reflective practitioners: competing with the dominant discourse
Authors: Corley Aileen , Eades Elaine
Published: March 2006

This article argues that discourse analysis can be utilized in conjunction with other forms of analysis to develop a more critical teaching and research agenda for Human Resource Development (HRD); in particular this article suggests that the introduction of a discourse analysis perspective can support and facilitate the development of critically reflective practitioners. The article highlights the tensions inherent within competing definitions of HRD and calls attention to the power of dominant discourse and argues that HRD needs to become more critical, opening up alternative discourses in order to support learning and critically reflective practice.
What about the managers? Contradictions between lifelong learning and management development
Authors: McCracken Martin , Winterton Jonathan
Published: March 2006

The policy priority of management development in the past 20 years appears to have been overshadowed since the new millennium by the goal of widening participation in learning of low‐skilled and excluded groups. This change of emphasis could potentially be damaging if efforts to increase management participation in learning are relaxed, because Britain's managers are still poorly qualified in comparison with other countries and managers play a key role in widening participation in learning at work. Research into barriers to learning amongst life assurance managers in Scotland has identified intrinsic and extrinsic factors affecting participation, suggesting a need for renewed efforts to ensure that management development remains a priority and that appropriate support is provided for learning at work.
Distribution of the F374 Allele of the SLC45A2 (MATP) Gene and Founder‐Haplotype Analysis
Authors: Yuasa I. , Umetsu K. , Harihara S. , Kido A. , Miyoshi A. , Saitou N. , Dashnyam B. , Jin F. , Lucotte G. , Chattopadhyay P. K. , Henke L. , Henke J.
Published: March 2006

The membrane‐associated transporter protein (MATP) plays an important role in melanin synthesis. The L374F mutation in the SLC45A2 gene encoding MATP has been suggested to be associated with skin colour in major human populations. In this study more detailed distribution of the F374 allele was investigated in 1649 unrelated subjects from 13 Eurasian populations and one African population. The highest allele frequency was observed in Germans (0.965); French and Italians showed somewhat lower frequencies; and Turks had an intermediate value (0.615). Indians and Bangladeshis from South Asia were characterized by low frequencies (0.147 and 0.059, respectively). We also found the F374 allele in some East and Southeast Asian populations, and explained this by admixture. Haplotype analysis revealed that the haplotype diversity was much lower in Germans than in Japanese, and suggest that the L374F mutation occurred only once in the ancestry of Caucasians. The large differences in distribution of the F374 allele and its haplotypes suggest that this allele may be an important factor in hypopigmentation in Caucasian populations.
Trophic ecology of East African caecilians (Amphibia: Gymnophiona), and their impact on forest soil invertebrates
Authors: Jones D. T. , Loader S. P. , Gower D. J.
Published: March 2006

Diets of the syntopic caecilian amphibians Boulengerula boulengeri and Scolecomorphus vittatus were studied from gut content analyses of 108 specimens collected from Nilo Forest Reserve, East Usambara Mountains, Tanzania. Head length and width relative to body length is greater in male B. boulengeri than in females, but no such dimorphism is apparent in S. vittatus. No differences, other than females consuming disproportionately more ants and invertebrate eggs and fewer termites than males, occur in the diets of B. boulengeri. The gut contents of S. vittatus are dominated by large, surface‐active earthworms, in contrast to those of B. boulengeri which contained smaller, endogeic earthworms and a much greater number and diversity of soil arthropods (particularly termites, ants and Diptera larvae). These dietary characteristics underline differences in microhabitat use between these caecilian species and thus corroborate a previously proposed hypothesis of niche separation. The ecological impact of caecilians and other limbless endogeic vertebrates is little studied and poorly known. Approximations based on current knowledge are not clear, but are interpreted as indicating that predation by caecilians is unlikely to be among the most important factors influencing population densities of soil‐dwelling termites and perhaps also ants: two groups recognized as soil ecosystem engineers.
Possible impact of snow depth and ungulate carcasses on red fox (Vulpes vulpes) populations in Norway, 1897–1976
Authors: Selås V. , Vik J. O.
Published: March 2006

During the 1900s, the number of red foxes Vulpes vulpes increased in northern Europe. At higher altitudes and latitudes, red fox populations are likely to be limited by thick snow cover, which makes small rodents less available. The negative effects of snow could, however, be compensated for by high ungulate numbers, because of increased availability of carcasses in snow‐rich winters. In the period 1897–1932, the number of foxes (mainly red foxes) killed was negatively related to snow depth indices in 13 of the 17 Norwegian counties. During 1947–1976, after a strong increase in ungulate and red fox numbers, the number of red foxes killed was negatively related to snow in only one county. The counties where ungulate density increased the most also had higher increases in the number of red fox bounties paid. The absence of large predators may at least partly be responsible for the strong increase in red fox populations, because eradication of large predators such as wolf Canis lupus in the late 1800s and early 1900s probably was a necessary condition for the strong increase in ungulate numbers, especially roe deer Capreolus capreolus.
Courtship and copulation, but not ejaculates, reduce the longevity of female field crickets (Gryllus bimaculatus)
Authors: Bateman P. W. , Ferguson J. W. H. , Yetman C. A.
Published: March 2006

Females of many taxa incur fitness costs from male sexual coercion and harassment leading to mating. Although male crickets cannot force copulations on females, female Gryllus bimaculatus in this study incurred significant reductions in longevity through being exposed to different levels of male courtship. Virgin females kept in isolation had the longest life spans. Reductions in longevity applied to females in sensory contact with males (without the opportunity to mate), females that courted and mated and females that mated but with fertilization being prevented. Females also incurred significant reductions in longevity when kept with other females, which may have been due to high levels of cannibalism. Consistent with previous studies, females appeared to incur no cost to longevity from receiving sperm or seminal fluid. It is known that female G. bimaculatus benefit genetically from multiple mating. However, this benefit could possibly be offset by the negative effect that male courtship and mating behaviour has on female longevity.
Home range, denning behaviour and microhabitat use of the carnivorous marsupial Dasyurus maculatus in eastern Australia
Authors: Glen A. S. , Dickman C. R.
Published: March 2006

Radio‐tracking of spotted‐tailed quolls Dasyurus maculatus (Marsupialia: Dasyuridae) in the forested ranges of north‐eastern New South Wales revealed that home ranges were extensive, with males occupying large, overlapping ranges [minimum convex polygon (MCP) up to 757 ha] and females occupying smaller, non‐overlapping territories (MCP up to 175 ha). Quolls were partly arboreal, although most activity occurred on the ground or on fallen logs. Hollow logs were most frequently used as dens, but rock crevices, burrows, tree hollows and artificial structures were also used. Individual quolls were located in up to nine different dens and, with the exception of maternal dens, rarely sheltered in the same location on successive days. The large home ranges of the spotted‐tailed quoll and the non‐overlapping nature of female ranges necessitate very large areas of habitat to support viable populations. Fallen timber, used extensively for shelter and in travelling, may serve to enhance the quality of habitat for the species, and should be retained by forest and wildlife managers.
Population dynamics of two sympatric antelope species, grey rhebok (Pelea capreolus) and mountain reedbuck (Redunca fulvorufula), in a highveld grassland region of South Africa
Authors: Taylor W. A. , Skinner J. D. , Williams M. C. , Krecek R. C.
Published: March 2006

Population dynamics of grey rhebok Pelea capreolus and mountain reedbuck Redunca fulvorufula were monitored at Sterkfontein Dam Nature Reserve in South Africa over three breeding seasons. Birth and death rates were recorded in both species, and causes of death were investigated. Immigration and emigration were monitored in grey rhebok. Grey rhebok bred seasonally, with 91% of lambs being born between November and February. The average fecundity rate was 74% and lamb sex ratios were 22M:19F. Mountain reedbuck also bred seasonally, with a birth peak between October and December. The average fecundity rate was 92%, and lamb sex ratios were 12M:8F. Most deaths in both species occurred between June and November each year. Sixteen grey rhebok deaths occurred during the study, of which 10 resulted from hypothermia during one spring snowfall event. This represented 27% of the population at the time. Males and females were affected to the same degree by the snow, but juveniles suffered more than adults. There was no evidence of infectious disease or predation. Forty‐three mountain reedbuck deaths occurred during the study, of which 32 resulted from hypothermia following the snowfall. This represented 51% of the population at the time. Females were affected by hypothermia more than males. There was no evidence of disease in the population from the examination of 41 culled animals, and no evidence of predation. Immigration and emigration within the grey rhebok population were uncommon, but dispersal of yearling males occurred every year between October and December when they were evicted from their natal herds. Herd structure of adult animals was very stable. In mountain reedbuck, emigration was very hard to detect.
Costs and benefits of flocking in foraging white‐fronted geese (Anser albifrons): effects of resource depletion
Authors: Amano T. , Ushiyama K. , Fujita G. , Higuchi H.
Published: March 2006

This study investigated the costs and benefits of flocking in white‐fronted geese Anser albifrons foraging on rice grains in Japan. The time budgets of focal geese were recorded, and the effects of flock size on the proportions of time spent in vigilant and agonistic behaviour were tested. The results showed that the decline in vigilance level and consequent increase in foraging time were beneficial results of flocking whereas agonistic interactions, a potential cost of flocking, did not increase with increasing flock size. However, seasonal variation in flock size suggested that exploitative competition could be a cost of flocking; the sizes of flocks in spring, when resource depletion had progressed, were significantly reduced compared with those in autumn. An experimental increase in rice density resulted in a significant increase in flock size. We conclude that the flock size of foraging white‐fronted geese is a result of compromise between a constant benefit of flocking (i.e. decline in vigilance level) and a cost of flocking varying with food abundance (i.e. exploitative competition).
Comparative signaling pathways of insulin‐like growth factor‐1 and brain‐derived neurotrophic factor in hippocampal neurons and the role of the PI3 kinase pathway in cell survival
Authors: Zheng Wen‐Hua , Quirion Rémi
Published: March 2006

Insulin‐like growth factor‐1 (IGF‐1) and brain‐derived neurotrophic factor (BDNF) are trophic factors required for the viability and normal functions of various neuronal cells. However, the detailed intracellular mechanism(s) involved in these effects in neuronal cells remains to be fully elucidated. In present study, the respective intracellular signaling pathway induced by IGF‐1 and BDNF and their possible role in neuronal survival were investigated. Both IGF‐1 and BDNF protected hippocampal neurons from serum deprivation‐induced death with IGF‐1 apparently being more potent. Western blot analyses showed that both IGF‐1 and BDNF induced the activation of the phosphatidylinositide 3 kinase (PI3)/Akt (protein kinase B) kinase and the mitogen‐activated protein kinase (MAPK) pathways. The phosphorylation of Akt and its downstream target, FKHRL1, induced by IGF‐1 was rapid and sustained while that of MAPK was transient. The reverse situation was observed for BDNF. Moreover, IGF‐1 potently induced the tyrosine phosphorylation of insulin receptor substrate‐1 (IRS‐1) and its association with PI3 kinase while BDNF was weak in these assays. In contrast, the tyrosine phosphorylation of Shc proteins was dramatically stimulated by BDNF, with IGF‐1 having only a minimal effect. Most interestingly, only the inhibitor of the PI3K/Akt pathway, LY294002, was able to block the survival effects of both IGF‐1 and BDNF; an inhibitor of the MAPK pathway inhibitor, PD98059, being ineffective. Taken together, these data reveal that the survival properties of both IGF‐1 and BDNF against serum deprivation are mediated by the activation of the PI3K/Akt, but not the MAPK, pathway in hippocampal neurons.
Anticonvulsant action of hippocampal dopamine and serotonin is independently mediated by D2 and 5‐HT1A receptors
Authors: Clinckers Ralph , Smolders Ilse , Meurs Alfred , Ebinger Guy , Michotte Yvette
Published: March 2006

The present microdialysis study evaluated the anticonvulsant activity of extracellular hippocampal dopamine (DA) and serotonin (5‐HT) with concomitant assessment of the possible mutual interactions between these monoamines. The anticonvulsant effects of intrahippocampally applied DA and 5‐HT concentrations were evaluated against pilocarpine‐induced seizures in conscious rats. DA or 5‐HT perfusions protected the rats from limbic seizures as long as extracellular DA or 5‐HT concentrations ranged, respectively, between 70–400% and 80–350% increases compared with the baseline levels. Co‐perfusion with the selective D2 blocker remoxipride or the selective 5‐HT1A blocker WAY‐100635 clearly abolished all anticonvulsant effects. These anticonvulsant effects were mediated independently since no mutual 5‐HT and DA interactions were observed as long as extracellular DA and 5‐HT levels remained within these protective ranges. Simultaneous D2 and 5‐HT1A receptor blockade significantly aggravated pilocarpine‐induced seizures. High extracellular DA (> 1000% increases) or 5‐HT (> 900% increases) concentrations also worsened seizure outcome. The latter proconvulsive effects were associated with significant increases in extracellular glutamate (Glu) and mutual increases in extracellular monoamines. Our results suggest that, within a certain concentration range, DA and 5‐HT contribute independently to the prevention of hippocampal epileptogenesis via, respectively, D2 and 5‐HT1A receptor activation.
NAAG peptidase inhibition reduces locomotor activity and some stereotypes in the PCP model of schizophrenia via group II mGluR
Authors: Olszewski Rafal T. , Bukhari Noreen , Zhou Jia , Kozikowski Alan P. , Wroblewski Jarda T. , Shamimi‐Noori Susan , Wroblewska Barbara , Bzdega Tomasz , Vicini Stefano , Barton Franca B. , Neale Joseph H.
Published: March 2006

Phencyclidine (PCP) administration elicits positive and negative symptoms that resemble those of schizophrenia and is widely accepted as a model for the study of this human disorder. Group II metabotropic glutamate receptor (mGluR) agonists have been reported to reduce the behavioral and neurochemical effects of PCP. The peptide neurotransmitter, N‐acetylaspartylglutamate (NAAG), is a selective group II agonist. We synthesized and characterized a urea‐based NAAG analogue, ZJ43. This novel compound is a potent inhibitor of enzymes, glutamate carboxypeptidase II (Ki = 0.8 nm) and III (Ki = 23 nm) that deactivate NAAG following synaptic release. ZJ43 (100 µm) does not directly interact with NMDA receptors or metabotropic glutamate receptors. Administration of ZJ43 significantly reduced PCP‐induced motor activation, falling while walking, stereotypic circling behavior, and head movements. To test the hypothesis that this effect of ZJ43 was mediated by increasing the activation of mGluR3 via increased levels of extracellular NAAG, the group II mGluR selective antagonist LY341495 was co‐administered with ZJ43 prior to PCP treatment. This antagonist completely reversed the effects of ZJ43. Additionally, LY341495 alone increased PCP‐induced motor activity and head movements suggesting that normal levels of NAAG act to moderate the effect of PCP on motor activation via a group II mGluR. These data support the view that NAAG peptidase inhibitors may represent a new therapeutic approach to some of the components of schizophrenia that are modeled by PCP.
Neurotrophin‐3 and a CREB‐mediated signaling pathway regulate Bcl‐2 expression in oligodendrocyte progenitor cells
Authors: Saini Harsimran S. , Gorse Karen M. , Boxer Linda M. , Sato‐Bigbee Carmen
Published: March 2006

Our previous results suggested that the transcription factor CREB mediates the actions of neuroligands and growth factor signals that coupled to different signaling pathways may play different roles along oligodendrocyte (OLG) development. We showed before that CREB phosphorylation in OLG progenitors is up‐regulated by neurotrophin‐3 (NT‐3); and moreover CREB is required for NT‐3 to stimulate the proliferation of these cells. We now show that treatment of OLG progenitors with NT‐3 is also accompanied by an increase in the levels of the anti‐apoptotic protein Bcl‐2. Interestingly, the presence of a putative CREB binding site (CRE) in the Bcl‐2 gene raised the possibility that CREB could also be involved in regulating Bcl‐2 expression in the OLGs. Supporting this hypothesis, the NT‐3 dependent increase in Bcl‐2 levels is abolished by inhibition of CREB expression. In addition, transient transfection experiments using various regions of the Bcl‐2 promoter and mutation of the CRE site indicate a direct role of CREB in regulating Bcl‐2 gene activity in response to NT‐3. Furthermore, protein‐DNA binding assays show that the CREB protein from freshly isolated OLGs indeed binds to the Bcl‐2 promoter CRE. Together with our previous results, these observations suggest that CREB may play an important role in linking proliferation and survival pathways in the OLG progenitors.
Distinct aggregation and cell death patterns among different types of primary neurons induced by mutant huntingtin protein
Authors: Tagawa Kazuhiko , Hoshino Masataka , Okuda Tomohiro , Ueda Hiroko , Hayashi Hiroshi , Engemann Sabine , Okado Haruo , Ichikawa Masumi , Wanker Erich E. , Okazawa Hitoshi
Published: March 2006

Aggregation of disease proteins is believed to be a central event in the pathology of polyglutamine diseases, whereas the relationship between aggregation and neuronal death remains controversial. We investigated this question by expressing mutant huntingtin (htt) with a defective adenovirus in different types of neurons prepared from rat cerebral cortex, striatum or cerebellum. The distribution pattern of inclusions is not identical among different types of primary neurons. On day 2 after infection, cytoplasmic inclusions are dominant in cortical and striatal neurons, whereas at day 4 the ratio of nuclear inclusions overtakes that of cytoplasmic inclusions. Meanwhile, nuclear inclusions are always predominantly present in cerebellar neurons. The percentage of inclusion‐positive cells is highest in cerebellar neurons, whereas mutant htt induces cell death most remarkably in cortical neurons. As our system uses htt exon 1 protein and thus aggregation occurs independently from cleavage of the full‐length htt, our observations indicate that the aggregation process is distinct among different neurons. Most of the neurons containing intracellular (either nuclear or cytoplasmic) aggregates are viable. Our findings suggest that the process of mutant htt aggregation rather than the resulting inclusion body is critical for neuronal cell death.
AMPA receptor activation, but not the accumulation of endogenous extracellular glutamate, induces paralysis and motor neuron death in rat spinal cord in vivo
Authors: Corona Juan Carlos , Tapia Ricardo
Published: March 2006

The mechanisms of motor neuron (MN) degeneration in amyotrophic lateral sclerosis (ALS) are unknown, but glutamate‐mediated excitotoxicity may be involved. To examine directly this idea in vivo, we have used microdialysis in the rat lumbar spinal cord and showed that four‐ to fivefold increases in the concentration of endogenous extracellular glutamate during at least 1 h, by perfusion with the glutamate transport inhibitor l‐2,4‐trans‐pyrrolidine‐dicarboxylate, elicited no motor alterations or MN damage. Stimulation of glutamate release with 4‐aminopyridine induced transitory ipsilateral hindlimb muscular twitches but no MN damage. In contrast, perfusion of α‐amino‐3‐hydroxy‐5‐methyl‐4‐isoxazole propionate (AMPA) did not modify glutamate levels but produced intense muscular spasms, followed by ipsilateral permanent hindlimb paralysis and a remarkable loss of MNs. These effects of AMPA were prevented by co‐perfusion with the AMPA receptor antagonist 2,3‐dihydroxy‐6‐nitro‐7‐sulfamoyl‐benzo(F)quinoxaline. Perfusion with NMDA or kainate produced no motor effects or MN damage. Thus, the elevation of endogenous extracellular glutamate in vivo due to blockade of its transport is innocuous for spinal MNs. Because this resistance is observed under the same experimental conditions in which MNs are highly vulnerable to AMPA, these results indicate that excitotoxicity due to this mechanism might not be an important factor in the pathogenesis of ALS.
Mutation of Trp84 and Asp313 of the dopamine transporter reveals similar mode of binding interaction for GBR12909 and benztropine as opposed to cocaine
Authors: Chen Nianhang , Zhen Juan , Reith Maarten E. A.
Published: March 2006

The different psychomotor‐stimulant effects of cocaine, GBR12909, and benztropine may partially stem from their different molecular actions on the dopamine transporter (DAT). To explore this possibility, we examined binding of these inhibitors to mutated DATs with altered Na+dependence of DAT activities and with enhanced binding of a cocaine analog, [3H]2β‐carbomethoxy‐3β‐(4‐fluorophenyl)tropane (CFT). In [3H]CFT competition assays with intact cells, the mutation‐induced change in the ability of Na+to enhance the apparent affinity of CFT, cocaine, GBR12909, and benztropine was inhibitor‐independent. Thus, for the four inhibitors, the curve of [Na+] versus apparent ligand affinity was steeper at W84L compared with wild type, shallower at D313N, and flat at W84LD313N. At each mutant, the apparent affinity of CFT and cocaine was enhanced regardless of whether Na+was present. However, the apparent affinity of GBR12909 and benztropine for W84L was reduced in the absence of Na+but near normal in the presence of 130 mmNa+, and that for D313N and W84LD313N was barely changed. At the single mutants, the alterations in Na+dependence and apparent affinity of the four inhibitors were comparable between [3H]CFT competition assays and [3H]dopamine uptake inhibition assays. These results demonstrate that DAT inhibitors producing different behavioral profiles can respond in an opposite way when residues of the DAT protein are mutated. For GBR12909 and benztropine, their cocaine‐like changes in Na+dependence suggest that they prefer a DAT state similar to that for cocaine. However, their cocaine‐unlike changes in apparent affinity argue that they, likely via their diphenylmethoxy moiety, share DAT binding epitopes that are different from those for cocaine.
Agonist‐independent internalization of metabotropic glutamate receptor 1a is arrestin‐ and clathrin‐dependent and is suppressed by receptor inverse agonists
Authors: Pula Giordano , Mundell Stuart J. , Roberts Peter J. , Kelly Eamonn
Published: March 2006

Three group I mGluR antagonists CPCCOEt, LY367385 and BAY36‐7620, were analyzed for their effect on cell surface expression of metabotropic glutamate receptor 1a and 1b. All three antagonists inhibited glutamate‐induced internalization of mGluR1a and mGluR1b. However, when added alone, either LY367385 or BAY36‐7620 increased the cell surface expression of mGluR1a but not mGluR1b. Both LY367385 and BAY36‐7620 displayed inverse agonist activity as judged by their ability to inhibit basal inositol phosphate accumulation in cells expressing the constitutively active mGluR1a. Interestingly, mGluR1a but not mGluR1b was constitutively internalized in HEK293 cells and both LY367385 and BAY36‐7620 inhibited the constitutive internalization of this splice variant. Furthermore, coexpression of dominant negative mutant constructs of arrestin‐2 [arrestin‐2‐(319–418)] or Eps15 [Eps15(EΔ95‐295)] increased cell surface expression of mGluR1a and blocked constitutive receptor internalization. In the presence of these dominant negative mutants, incubation of cells with LY367385 and BAY36‐7620 produced no further increase in cell surface expression of mGluR1a. Taken together, these results suggest that the constitutive activity of mGluR1a triggers the internalization of the receptor through an arrestin‐ and clathrin‐dependent pathway, and that inverse agonists increase the cell surface expression of mGluR1a by promoting an inactive form of mGluR1a, which does not undergo constitutive internalization.
Stress induces activation of stress‐activated kinases in the mouse brain
Authors: Liu Ya Fang , Bertram Kurt , Perides George , McEwen Bruce S. , Wang Dechun
Published: March 2006

Stress is a part of daily life. However, molecular mechanisms underlying the activation of limbic‐hypothalamic‐pituitary‐adrenal (LHPA) axis remains unknown. In this study, we explored whether activation of the mitogen‐activated kinase kinase 4 (MKK4)‐c‐Jun‐N‐terminal kinase (JNK) signaling pathway may play a role in the activation of the LHPA axis. We found that forced‐swim stress induced elevation of activated MKK4 in the hippocampal formation, amygdala, and hypothalamus. Unlike MKK4, a high basal level of JNK activity is present in many brain areas of unstressed mice. Forced‐swim stress significantly elevated JNK activity in the hypothalamus and amygdala and, to a lesser extent, in the cortex, CA1 and CA3 regions, and the dentate gyrus. To further investigate the role of MKK4 and JNK in induction of stress responses, we investigated whether a different stress, namely, restraint stress, induced activation of MKK4 or JNK in the brain. We found that restraint stress also induced elevation of activated MKK4 and JNK in the hippocampal formation, amygdala, and hypothalamus. Because MKK4 and JNK were activated within 5 min following stress, we propose that the MKK4‐JNK signaling may be an early neural event in the initiation of neuroendocrine, autonomic and behavioral stress responses.
Nitric oxide‐induced cell death of cerebrocortical murine astrocytes is mediated through p53‐ and Bax‐dependent pathways
Authors: Yung Hong Wa , Bal‐Price Anna K. , Brown Guy C. , Tolkovsky Aviva M.
Published: March 2006

We have investigated the mechanism by which nitric oxide (NO) induces the death of mouse astrocytes. We show that NO (from donor diethylenetriamine‐NO adduct) induces death with several features of apoptosis, including chromatin condensation, phosphatidylserine exposure on the outer leaflet of the plasma membrane, Bax translocation to the mitochondria and cytochromecrelease, but no caspase activation or nuclear fragmentation is observed. Nitric oxide also elevates p53 expression, causing a concomitant increase in p53 serine 18 phosphorylation and p53 translocation from the cytoplasm to the nucleus. Activation of Bax and p53 is important for NO‐induced apoptosis‐like cell death because Bax‐ or p53‐deficient astrocytes are much more resistant than wild‐type cells to the same NO treatment. We further demonstrate that LY294002‐sensitive kinases are responsible for controlling serine 18 phosphorylation of p53, thereby regulating the pro‐apoptotic activity of p53 in astrocytes. While apoptosis is suppressed in the presence of LY294002, however, death by necrosis is increased, suggesting that LY294002‐sensitive kinases additionally suppress a latent necrotic response to NO. We conclude that NO‐induced death in astrocytes is mediated by p53‐ and Bax‐dependent mechanisms, although full manifestation of apoptosis is aborted by concomitant inhibition of caspase activation. More generally, our data suggest that apoptotic mediators should be evaluated as the cause of cell death even in cases where a full apoptotic phenotype is lacking.
Genetic ablation of tumor necrosis factor‐alpha (TNF‐α) and pharmacological inhibition of TNF‐synthesis attenuates MPTP toxicity in mouse striatum
Authors: Ferger Boris , Leng Andreas , Mura Anna , Hengerer Bastian , Feldon Joram
Published: March 2006

The impact of pro‐inflammatory cytokines such as tumor necrosis factor‐α (TNF‐α) in the pathology of Parkinson's disease (PD) and in MPTP neurotoxicity remains unclear. Here, male TNF‐α (–/–) deficient mice and C57bL/6 mice were treated with MPTP (4 × 15mg/kg, 24 h intervals) and in one series, thalidomide was administered to inhibit TNF‐α synthesis. Real‐time RT‐PCR revealed that the striatal mRNA levels of TNF‐α, of the astrocytic marker glial fibrillary acidic protein (GFAP) and of the marker for activated microglia, macrophage antigen complex‐1 (MAC‐1), were significantly enhanced after MPTP administration. Thalidomide (50 mg/kg, p.o.) partly protected against the MPTP‐induced dopamine (DA) depletion, and TNF‐α (–/–) mice showed a significant attenuation of striatal DA and DA metabolite loss as well as striatal tyrosine hydroxylase (TH) fiber density, but no difference in nigral TH and DA transporter immunoreactivity. TNF‐α deficient mice suffered a lower mortality (10%) compared to the high mortality (75%) seen in wild‐type mice after acute MPTP treatment (4 × 20mg/kg, 2 h interval). HPLC measurement of MPP+ levels revealed no differences in TNF‐α (–/–), wild‐type and thalidomide treated mice. This study demonstrates that TNF‐α is involved in MPTP toxicity and that inhibition of TNF‐α response may be a promising target for extending beyond symptomatic treatment and developing anti‐parkinsonian drugs for the treatment of the inflammatory processes in PD.
Motor activity and gene expression in rats with neonatal 6‐hydroxydopamine lesions
Authors: Masuo Yoshinori , Ishido Masami , Morita Masatoshi , Oka Syuichi , Niki Etsuo
Published: March 2006

A rat model of a hyperkinetic disorder was used to investigate the mechanisms underlying motor hyperactivity. Rats received an intracisternal injection of 6‐hydroxydopamine on post‐natal day 5. At 4 weeks of age, the animals showed significant motor hyperactivity during the dark phase, which was attenuated by methamphetamine injection. Gene expression profiling was carried out in the striatum and midbrain using a DNA macroarray. In the striatum at 4 weeks, there was increased gene expression of the NMDA receptor 1 and tachykinins, and decreased expression of a GABA transporter. At 8 weeks, expression of the NMDA receptor 1 in the striatum was attenuated, with enhanced expression of the glial glutamate/aspartate transporter. In the midbrain, a number of genes, including the GABA transporter gene, showed decreased expression at 4 weeks. At 8 weeks, gene expression was augmented for the dopamine transporter, D4 receptor, and several genes encoding peptides, such as tachykinins and their receptors. These results suggest that in the striatum the neurotransmitters glutamate, GABA and tachykinin may play crucial roles in motor hyperactivity during the juvenile period. Several classes of neurotransmitters, including dopamine and peptides, may be involved in compensatory mechanisms during early adulthood. These data may prompt further neurochemical investigations in hyperkinetic disorders.
Kainate seizures increase nociceptin/orphanin FQ release in the rat hippocampus and thalamus: a microdialysis study
Authors: Aparicio Liliana Carmona , Candeletti Sanzio , Binaschi Anna , Mazzuferi Manuela , Mantovani Simona , Di Benedetto Manuela , Landuzzi Daniela , Lopetuso Giuseppe , Romualdi Patrizia , Simonato Michele
Published: March 2006

The neuropeptide nociceptin/orphanin FQ (N/OFQ) has been suggested to play a facilitatory role in kainate seizure expression. Furthermore, mRNA levels for the N/OFQ precursor are increased following kainate seizures, while its receptor (NOP) density is decreased. These data suggest increased N/OFQ release. To obtain direct evidence that this is the case, we have developed a microdialysis technique, coupled with a sensitive radioimmunoassay, that allows measurement of N/OFQ release from the hippocampus and thalamus of awake, freely moving animals. In both these brain areas, the spontaneous N/OFQ efflux decreased by approximately 50% and 65% when Ca2+ was omitted and when tetrodotoxin was added to the perfusion medium, respectively. Perfusion of the dialysis probe with high K+increased N/OFQ release (approximately threefold) in a Ca2+‐dependent and tetrodotoxin‐sensitive manner. Kainate seizures caused a twofold increase in N/OFQ release followed, within 3 h, by a return to baseline levels. Approximately 5 h after kainate, a late increase in N/OFQ release was observed. On the following day, when animals were having only low grade seizures, N/OFQ release was not significantly different from normal. These phenomena were observed with similar patterns in the hippocampus and in the thalamus. The present data indicate that acute limbic seizures are associated with increased N/OFQ release, which may prime the molecular changes described above, i.e. cause down‐regulation of NOP receptors and activation of N/OFQ biosynthesis.