Biomedical subjects

Enrico Alleva

Publications and source records attributed to Enrico Alleva.

34 records · Page 2Linked to original sources

PubMed2004

Scopolamine effects on ultrasonic vocalization emission and behavior in the neonatal mouse.

Developmental alterations of the cholinergic system can lead to short- and long-term detrimental consequences for brain function. In order to study the cholinergic modulation of behavior in the neonatal mouse, we characterized ultrasonic vocalizations and spontaneous behavior of 5- and 8-day old CD-1 Swiss mice after i.p. administration of the muscarinic antagonist scopolamine (doses, 0.8 and 2 mg/kg) during both a first isolation of 30 min and a re-isolation of 5 min, occurring immediately after a brief reunion with the mother. As concerns the first isolation, on PND 5, only scopolamine 0.8m g/kg increased the number of ultrasonic vocalizations and, on PND 8, both doses increased it in a dose-dependent fashion. Scopolamine effects on spontaneous behavior were very limited on PND 5, but markedly evident on PND 8, the high dose increasing activity profile. Independently from treatment, the brief reunion with the mother had no effects on mouse ultrasound emission during re-isolation. The present results show that the cholinergic system plays a role in inhibiting rodent pup USV emission and spontaneous behavior and suggest that the analysis of spontaneous behavior and, in particular, of the number of ultrasonic vocalizations represents a valuable tool to detect precocious developmental alterations of the cholinergic function in the mouse, the most used animal species to model human health disorders.

Age Factors↗

PubMed2004

Neonatal behaviors associated with ultrasonic vocalizations in mice (mus musculus): A slow-motion analysis.

Infant rodents emit ultrasonic vocalizations (USVs) when isolated from the mother and littermates. While USVs reportedly promote maternal behavior, their communicatory role is still controversial. We performed a detailed behavioral characterization in 7-day-old CD-1 Swiss mice to describe (a) behavioral patterns accompanying or immediately preceding or following the USV and (b) how selected USV features are modulated according to the behavioral pattern being performed. The present results represent an ethogram of mouse pup behavior in close temporal proximity to USV, providing further information to evaluate the functional role of USVs in the framework of the mother-offspring relationship. A significant increase of head rising behavior immediately prior to the USV and a behavioral activation displayed by pups in conjunction with it suggest that pups behave in a way that may favor interaction with their mothers.

Animal Communication↗

PubMed2004

Intrahippocampal administration of BDNF in adult rats affects short-term behavioral plasticity in the Morris water maze and performance in the elevated plus-maze.

The present study evaluated the effects of a single intrahippocampal administration of brain-derived neurotrophic factor (BDNF) on memory retention in a water maze. Adult rats were trained in a water maze (acquisition phase, day 1). Immediately after the last training trial subjects were injected in the right hippocampus with either BDNF (24 microg) or phosphate-buffered saline (1 microl). On day 2, all subjects were tested for memory retention in a probe trial and were subsequently tested for reversal learning. While no differences emerged in the probe trial, BDNF-treated subjects showed a shorter latency and a shorter path length to reach the platform during the reversal phase. A significant difference in their "turn angle" and in their swim paths suggests that they might have used a different search strategy compared with controls. Moreover, all subjects also underwent an elevated-plus maze test. BDNF-treated-animals showed a clear tendency to spend a greater amount of time in the open arms and a significantly higher frequency of grooming behavior and of the stretched-attend posture in this maze area, but no differences in locomotion. Overall, these results indicate that administration of BDNF improves performance in a spatial memory task and has enduring effects on emotional behavior.

Animals↗

PubMed2004

Long-term effects of the periadolescent environment on exploratory activity and aggressive behaviour in mice: social versus physical enrichment.

The aims of the present study were (i) to investigate the effects of environmental enrichment during periadolescence on different behavioural and neurochemical responses in male CD-1 mice at adulthood and (ii) to describe the relative role of the physical and social components of the enrichment in producing these effects. Thirty 5-day-old mice were randomly assigned to one of the following housing conditions lasting five consecutive days: (i) individually housed in a standard cage, (ii) housed in pairs in a standard cage, (iii) individually housed in a physically enriched cage, and (iv) housed in pairs in a physically enriched cage. At adulthood, 80 days after the enrichment exposure, the explorative behaviour in an open field, as well as the behaviour in agonistic encounters, was evaluated in association with the analysis of selected central (hypothalamic levels of nerve growth factor (NGF) and brain-derived growth factor(BDNF)) and peripheral (plasma corticosterone levels) biochemical parameters. The results show that the long-term effects of the physical and the social enrichment are different and not additive. In particular, while social enrichment by itself exerted very limited effects, physical enrichment decreased the exploratory activity and altered social behaviour. Mice housed in pairs in an enriched cage showed low activity levels in the open field, and they tended to become more frequently dominant, although showing a more affiliative and less aggressive social interaction strategy. Furthermore, they presented low levels of hypothalamic NGF and high levels of brain-derived growth factor, suggesting an important effect of the combination of social and physical enrichment on neurobehavioral markers of brain plasticity and on animal ability to cope with social challenges.

Aggression↗

PubMed2004

Neurobehavioral coping to altered gravity: endogenous responses of neurotrophins.

An altered gravitational environment represents a unique challenge for biological systems that have evolved against gravitational background. Ground-based and space research indicates that the developing nervous system is potentially affected by exposure to hyper/microgravity. With the construction of the orbiting International Space Station long-term research on the nervous system will be possible. With this perspective, we started ground-based studies to characterize mouse behavioral responses to rotation-induced 2 g hypergravity, using a custom-made centrifuge device. Brain levels of nerve growth factor (NGF) and brain-derived neurotrophic factor (BDNF) as well as NGF and BDNF expression and mast cell distribution in heart and lung, were evaluated and correlated with the changes in mouse behavior upon hypergravity exposure. Hypergravity strongly affected the spontaneous activity of the animals, selectively modifying mouse behavioral repertoire. Such changes were mainly related to variations in brain levels of NGF, while BDNF was slightly affected, thus confirming a role for these neurotrophins in neuronal plasticity underlying experience-induced neurobehavioral changes. Moreover, gender differences were observed in both behavioral and neurobiological responses to hypergravity. These results indicate that changes in the gravitational environment might represent a useful tool to investigate the neurobiological and behavioral responses to stressors and may provide insights into the mechanisms underlying development and plasticity of nervous system in brain, heart, and lung.

Animals↗

PubMed2004

Transgenic mouse in vivo library of human Down syndrome critical region 1: association between DYRK1A overexpression, brain development abnormalities, and cell cycle protein alteration.

Down syndrome is the most frequent genetic cause of mental retardation, having an incidence of 1 in 700 live births. In the present study we used a transgenic mouse in vivo library consisting of 4 yeast artificial chromosome (YAC) transgenic mouse lines, each bearing a different fragment of the Down syndrome critical region 1 (DCR-1), implicated in brain abnormalities characterizing this pathology. The 152F7 fragment, in addition to genes also located on the other DCR-1 fragments, bears the DYRK1A gene, encoding for a serine-threonine kinase. The neurobehavioral analysis of these mouse lines showed that DYRK1A overexpressing 152F7 mice but not the other lines display learning impairment and hyperactivity during development. Additionally, 152F7 mice display increased brain weight and neuronal size. At a biochemical level we found DYRK1A overexpression associated with a development-dependent increase in phosphorylation of the transcription factor FKHR and with high levels of cyclin B1, suggesting for the first time in vivo a correlation between DYRK1A overexpression and cell cycle protein alteration. In addition, we found an altered phosphorylation of transcription factors of CREB family. Our findings support a role of DYRK1A overexpression in the neuronal abnormalities seen in Down syndrome and suggest that this pathology is linked to altered levels of proteins involved in the regulation of cell cycle.

Animals↗

PubMed2004

Rhes is involved in striatal function.

The development and the function of central nervous system depend on thyroid hormones. In humans, the lack of thyroid hormones causes cretinism, a syndrome of severe mental deficiency. It is assumed that thyroid hormones affect the normal development and function of the brain by activating or suppressing target gene expression because several genes expressed in the brain have been shown to be under thyroid hormone control. Among these, the Rhes gene, encoding a small GTP-binding protein, is predominantly expressed in the striatal region of the brain. To clarify the role of Rhes in vivo, we disrupted the Rhes gene by homologous recombination in embryonic stem cells and generated mice homozygous for the Rhes null mutation (Rhes(-/-)). Rhes(-/-) mice were viable but weighed less than wild-type mice. Furthermore, they showed behavioral abnormalities, displaying a gender-dependent increase in anxiety levels and a clear motor coordination deficit but no learning or memory impairment. These results suggest that Rhes disruption affects selected behavioral competencies.

Age Factors↗

PubMed2004

Introductory keynote. The state of the art in animal experimentation.

This issue of Annali dell'Istituto Superiore di Sanità critically evaluates the progression in the ethical relationship between humans and animals (i.e., between biomedical researchers and laboratory animals). The main goal of this publication is in fact to provide a basis for an in-depth discussion of highly debated topics in the contemporary bioethics of animal experimentation, with particular focus on ethological issues and the question of minimal sample size and its contribution to reducing the number of experimental animals. The ethological issues addressed in this publication cover all behavioural patterns specifically moulded by the phylogenetic and ontogenetical history of a given species, a perspective that is often neglected when discussing the promotion of animal welfare.

Animal Experimentation↗

PubMed2003

Prolonged perinatal AZT administration and early maternal separation: effects on social and emotional behaviour of periadolescent mice.

Zidovudine (AZT) is an effective treatment in preventing perinatal transmission of HIV-1; however, a continuous re-evaluation of the risk-benefit ratio of human exposure to this drug is suggested by both clinical and animal studies. The objective of this study was to assess the medium and long-term effects of pre-postnatal AZT treatment on mouse social and emotional behaviour and the possible interactions between AZT exposure and disruptions in the mother-infant relationship. Pregnant CD-1 mice were administered per os with AZT (160 mg/kg) from pregnancy day 10, throughout delivery, to lactation day 10. In half of the litters, the offspring was separated from the mother for 3 h from postnatal days 2 (PND2) to PND14. On PND35, a 30-min social interaction test was performed and corticosterone levels were measured at the end of the session. On PND80, long-term effects of AZT on emotionality were assess by means of an elevated plus-maze. Results indicate that, on PND35, previous AZT exposure affected social behaviour of the experimental subjects, reducing aggressive interactions in males, while decreasing investigative behaviours in females. At adulthood, AZT inhibited exploratory behaviour in the plus-maze while increasing the frequency of risk-assessment postures in male mice. As for maternal deprivation, this early manipulation exerted a pro-aggressive effect in adolescent male mice, deprived subjects being overall characterised by higher activity levels and a deficit in habituation, an effect also observed in the plus-maze. A significant interaction between AZT and maternal deprivation was found for affiliative behaviours. As for corticosterone levels, no AZT effect was found, while maternal deprivation tended to reduce elevations of this hormone in response to stressful stimuli. Overall results from this study indicate that both AZT exposure and maternal deprivation induced gender-dependent changes in social and emotional behaviour both during adolescence and at adulthood.

Animals↗

PubMed2003

Polybrominated diphenyl ethers: neurobehavioral effects following developmental exposure.

Polybrominated diphenyl ethers (PBDEs), a class of widely used flame retardants, are becoming widespread environmental pollutants, as indicated by studies on sentinel animal species, as well as humans. Of particular concern are the reported increasingly high levels of PBDEs in human milk, as should be given that almost no information is available on their potential effects on developing organisms. In order to address this issue, studies have been conducted in mice and rats to assess the potential neurotoxic effects of perinatal exposure to PBDEs (congeners 47, 99, 153 and the penta-BDE mixture DE-71). Characteristic endpoints of PBDE neurotoxicity are, among others, endocrine disruption (e.g. decreased thyroid hormone levels), alteration in cholinergic system activity (behavioral hyporesponsivity to nicotine challenge), as well as alterations of several behavioral parameters. In particular, the main hallmark of PBDE neurotoxicity is a marked hyperactivity at adulthood. Furthermore, a deficit in learning and memory processes has been found at adulthood in neonatally exposed animals. Some of neurotoxic effects of PBDEs are comparable to those of polychlorinated biphenyls (PCBs), though the latter class of compounds seems to exert a stronger toxic effect. Available information on PBDE neurotoxicity obtained from animal studies and the possibility of neonatal exposure to PBDEs via the mother's milk suggest that these compounds may represent a potential risk for neurobehavioral development in humans.

Animals↗

PubMed2003

Agonistic encounters in aged male mouse potentiate the expression of endogenous brain NGF and BDNF: possible implication for brain progenitor cells' activation.

The condition of dominance or submission following agonistic encounters in the adult male mouse is known to differentially affect brain nerve growth factor, a neurotrophin playing a role in brain remodeling, in the fine tuning of behaviour and in the regulation of the basal forebrain cholinergic neurons. During development and adult life nerve growth factor regulates brain expression of neurotransmitters and the stimulation of progenitor cells (stem cells) which, under different external stimuli, may differentiate into neuronal and/or glial cells promoting the recovery of the injured brain. However, little information is available for the aged brain. Thus in the present study we investigated the effect of the social status ('dominance' vs. 'submission') in the aged mouse on the presence of nerve growth factor, brain-derived neurotrophic factor, choline acetyltransferase, neuropeptide Y and progenitor cells of selected brain regions. We found that aged dominant mice showed increased brain-derived neurotrophic factor in the subventricular zone and hippocampus and increased choline acetyltransferase in the septum and basal nuclei, which were associated with increased presence of progenitor cells in the subventricular zone. Conversely, in aged subordinate mice the data showed a marked brain increase in nerve growth factor in the subventricular zone and hippocampus, choline acetyltransferase in the septum and basal nuclei and neuropeptide Y in the hippocampus and parietal cortex. The possible functional implications of these findings are discussed.

Aging↗

PubMed2002

Effects of perinatal exposure to a polybrominated diphenyl ether (PBDE 99) on mouse neurobehavioural development.

Polybrominated diphenyl ethers (PBDEs), a class of widely used flame retardants, are extensively diffused in the environment as shown by several studies on sentinel animal species, as well as humans. Of particular concern are the reported high levels of PBDEs in human milk, as almost no information is available on their potential effects on developing organisms. We investigated the effects of perinatal PBDE exposure on mouse neurobehavioural development. 2,2',4,4,5-pentabromodiphenylether (PBDE 99; 0.6, 6 and 30 mg/kg per day) was administered daily to CD-1 Swiss females by gavage from gestational day (GD) 6 to postnatal day (PND) 21. Aroclor 1254 (A1254; 6 mg/ kg per day), a PCB mixture, was administered following the same schedule and served as a positive controL The PBDE 99 medium dose had an effect on litter viability. Sensori-motor development analysis (PNDs 2-20) revealed a delayed appearance of climbing response in the PBDE 99 high-dose group. On PND 11, the homing test revealed a trend for treated animals, particularly the A1254 group, to be more active than controls. This activity level alteration was strongly increased on PNDs 34 and 60 in an open-field arena. On PND 60, treated mice showed also an altered thigmotaxis, spending more time in the centre of the arena than controls. At adulthood, A1254 treated mice were still hyperactive, whereas the PBDE 99 groups tended to be hypoactive. These findings showed that perinatal exposure to PBDE 99 produces several behavioural alterations and that its effects are not always similar to those of A1254. The possibility of exposure of neonates to PBDEs warrants further studies to characterise their developmental neurotoxicity.

Animals↗

PubMed2002

Animal models of anti-HIV drugs exposure during pregnancy: effects on neurobehavioral development.

In the last 10 years, zidovudine (AZT) has become the main prophylactic therapy against vertical HIV-1 transmission. AIDS Clinical Trials Group (ACTG) 076 have demonstrated that the administration of AZT to HIV-infected women during their third trimester of pregnancy, trough labor and given orally to babies for 6 weeks, reduced by two-thirds the rate of vertical infection. Although the rapid diffusion of this regimen into clinical practice together with the implementation of HIV counseling and testing practices have dramatically reduced the vertical transmission rate in the US and Western Europe, there is a growing concern on the adverse effects of antiretroviral therapy on the fetus and the newborn. In fact, even though shorter regimen therapies that are less complex and expensive to implement in poor countries have been demonstrated as effective as ACTG 076 regimen, the distribution of the risk of vertical transmission in the developing countries is still very high. Consequently, a large number of unborns will be a candidate to developmental exposure to antiretroviral agents. To date, data on the transplacental mutagenicity, carcinogenicity and mitochondrial dysfunction induced by developmental exposure to AZT have been reported in several animal models. Furthermore, one study reported severe yet few human cases of cardiomyopathy and neurological disease likely associated with mitochondrial dysfunction in uninfected infants of seropositive mothers perinatally exposed to AZT. For all of these reasons, many investigations have been focusing on the assessment of the potential adverse effects of nucleoside reverse transcriptase (RT) inhibitors (NRTI) administration during development. A survey of the main results derived from clinical and animal studies is reported here, focusing on those neurobehavioral studies that have been looking for specific and/or aspecific changes in the nervous system induced by NRTI exposure in utero.

Animals↗

PubMed2002

A new easy accessible and low-cost method for screening olfactory sensitivity in mice: behavioural and nociceptive response in male and female CD-1 mice upon exposure to millipede aversive odour.

In a previous study, mice were found to be repelled by the odour emitted by the millipede (Ommatoiulus sabulosus) as a defensive strategy against predators [Physiol. Behav. 74 (2001) 305-311]. To develop a standardised test for screening olfactory capabilities in rodents, we have characterised the behavioural response displayed by adult male and female CD-1 mice when exposed to a Stimulus Object (SO) consisting of a millipede-shaped sponge previously soaked either in a Toluquinone (TQ) solution (5g/100ml; Fluka), a chemical component of the exudate secreted by the millipede, or in distilled water. In Experiment 1, behaviours performed when exposed to the SO were scored (15min for 5 consecutive days). TQ exposure suppressed nearly completely Catching and Eating the SO, and increased general activity in a sex-dependent fashion. In Experiment 2, performances in a hot-plate test (50+/-0.5 degrees C, cut-off 60s) were assessed immediately after a 15-min exposure to the SO. Toluquinone-exposed mice showed a subtle yet significant decrease of pain threshold. TQ exposure assay is a new, easily testable, and low-cost method for measuring rodents olfactory sensitivity relevant for the analysis of the pharmacological agents, lesions and transgenesis.

Animals↗

PubMed2002

Short-term hypergravity influences NGF and BDNF expression, and mast cell distribution in the lungs and heart of adult male mice.

In this study we investigate the effects of short-term hypergravity on lung and heart neurotrophins and mast cell distribution. Our results showed that brain derived-neurotrophic factor (BDNF) protein and mRNA expression are increased in the lungs of mice exposed to hypergravity while in the heart hypergravity causes a marked reduction in BDNF mRNA expression, and a decrease in BDNF protein. Compared to controls, nerve growth factor (NGF) protein was expressed more in the heart of rotated mice. These observations demonstrate that altered hypergravity can affect, though differentially, the local expression of NGF and BDNF proteins and their mRNAs in the lung and heart and indicates that short-term exposure to hypergravity causes a marked increase in BDNF, but not in NGF in the lungs of adult mice. Moreover, mast cells, which are NGF-producing cells and implicated in cardiac and respiratory activity, increased in number in proximity to blood vessels in the heart and in lung airway epithelium of rotated mice. This study indicates that hypergravity influences cardiovascular and respiratory tissue and suggests a neurotrophin involvement in the reaction to this environmental exposure.

Animals↗

PubMed2002

Neurobehavioural responses to hypergravity environment in the CD-1 mouse.

Behavioural responses of CD-1 mice exposed to 2 g hypergravity (HG; 60 or 120 min) were investigated during adolescence and at adulthood. To characterise motion sickness (MS), pica behaviour, a reliable MS index measured through kaolin consumption, and spontaneous activity were evaluated before, during and after HG exposure. Short- and/or long-lasting effects on emotional responses, exploratory behaviour and spatial learning performances were also investigated and brain levels of nerve growth factor (NGF) and brain derived neurotrophic factor (BDNF) assessed. An increased pica behaviour during post rotational days and a reduction in spontaneous activity during rotation indicated a mild sickness associated with HG, and susceptibility to MS was sex and age related. Short- and long-lasting effects of exposure were also observed, rotated mice showing altered emotional/anxiety behavioural profiles and impaired spatial learning performances. Moreover, central NGF levels were markedly increased after rotation, while minor changes were observed in BDNF levels.

Research Support, Non-U.S. Gov't↗