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Biomedical subjects

E Alleva

Publications and source records attributed to E Alleva.

At least 19 recordsLinked to original sources

Organochlorine and heavy-metal contaminants in wild mammals and birds of Urbino-Pesaro Province, Italy: an analytic overview for potential bioindicators.

Tissue samples from 56 bird and 11 mammal species of different trophic levels, collected from 1994 to 1995 from the Urbino-Pesaro area in the Marche region of central Italy, were analyzed for the presence of organochlorine compounds (polychlorinated biphenyls and p,p'-DDE) and heavy metals (Pb, Cd, Cr, and Hg). Results revealed interspecies differences in pollutant residue concentrations. A clear relationship between contaminant and trophic levels emerged depending on several factors specific to the chemicals and the organisms, the importance of dietary accumulation, and metabolic capacity as it increased toward higher trophic levels. Polychlorinated biphenyls and p,p'-DDE were found in all of the bird and mammal species analyzed (bird- or fish-eating birds), and insectivore mammals showed the highest level of these contaminants. Pb and Hg residues were also widely detected and reflected trophic-level differences. The highest concentration of Pb was found in herbivorous or bird-eating aquatic invertebrates and in insectivorous mammals, particularly in the hedgehog (Erinaceus europaeus), whereas the highest Hg levels were found in fish-eating birds. All of the other heavy metals were detected at low concentrations and represented background levels for birds and mammals, with the exception of increased amounts of Cd and Cr, respectively, found in stone marten (Martes foina) and fox (Vulpes vulpes). Data from this study provided information on baseline levels of interest to monitor status and trends in chemical residue in biota in this specific area, and therefore they represent a tool to evaluate potential ecologic, wildlife, and human health exposure.

Adipose Tissue↗

Spatial memory deficits in middle-aged mice correlate with lower exploratory activity and a subordinate status: role of hippocampal neurotrophins.

The aim of the present work was to relate age-related individual differences in cognitive function with behavioural strategies employed in social and non-social challenges. To this purpose, the behaviour of adult (5-month-old) and middle-aged (13-month-old) CD-1 mice was scored in the social interaction, plus-maze, Morris water maze (MWM) and open-field tests. In addition, brain levels of nerve growth factor and brain-derived neurotrophic factor (BDNF) were analysed and correlated with the behaviours scored. Compared to adults, middle-aged mice showed greater anxiety in both non-social and social situations, spending less time in the open arms of the plus-maze and performing more freezing behaviour in response to aggression. Based upon their behaviour in the social interaction test, adult and middle-aged subjects were classified as dominant or subordinate and their behaviour in the open field, plus-maze and MWM tests subjected to factor analysis, taking into account age and social status. Results highlighted meaningful differences in exploratory strategies as a function of social status only in middle-aged subjects. In particular, middle-aged dominants were, overall, more explorative than same-aged subordinates, spending less time in peripheral areas and approaching more readily a novel object. Interestingly, in middle-aged mice, superior performance in the MWM task was associated with exploratory strategies exploited by dominants. At adulthood, BDNF hippocampal levels, but not specific behaviours, were positively correlated with the ability to learn a spatial task. Overall, data indicate that, in middle-aged subjects individual differences in exploratory strategies, rather than neurotrophin levels, are able to predict the degree of impairment in a spatial learning task.

Age Factors↗

The endocrine disruptor atrazine accounts for a dimorphic somatostatinergic neuronal expression pattern in mice.

It has now been established that a large number of man-made and natural chemicals are capable of interfering with the action of natural hormones. In this category "endocrine disruptors" such as the herbicide atrazine, when administered at ecological low doses (1 or 100 microg/kg per day) from gestational day 14 to postnatal day 21, provided a clear dimorphic neurodegenerative pattern in some brain areas of the domestic mouse (Mus musculus). Indeed, the high concentration (100 microg/kg per day) with respect to the low concentration (1 microg/kg per day) induced relevant neuronal damage in extrahypothalamic sites, such as the cortical and striatal areas in both sexes. Marked alterations in other areas, including the hippocampal and hypothalamic nuclei, were mostly typical of the female. At the neuronal level, the neuropeptide somatostatin, specific for the secretion of growth hormone, seemed to be a major target of atrazine effects, as demonstrated by evident subtype2,3,5 receptor mRNA differences of this neuropeptide, at least for the first two subtypes. In particular, a very strong (p < 0.001) upregulation of subtype2 expressing neurons was detected in female hypothalamic areas, specifically the suprachiasmatic nucleus, whereas a similar downregulatory trend was reported for some extrahypothalamic areas such as the striatum. Interestingly, very strong upregulatory and downregulatory actions were detected for neurons expressing subtype3 in male hypothalamic and amygdalar regions and in the cortical and hippocampal areas, respectively. Overall, it appears that these first neurotoxicological effects of atrazine are very likely linked to dimorphic expression patterns of specific somatostatin subtypes in discrete but key hypothalamic and extrahypothalamic areas of Mus musculus.

Animals↗

Sub-neurotoxic neonatal anoxia induces subtle behavioural changes and specific abnormalities in brain group-I metabotropic glutamate receptors in rats.

Anoxia in the first week of life can induce neuronal death in vulnerable brain regions usually associated with an impairment of cognitive function that can be detected later in life. We set-up a model of subneurotoxic anoxia based on repeated exposures to 100% nitrogen during the first 7 days of post-natal life. This mild post-natal exposure to anoxia specifically modified the behaviour of the male adult rats, which showed an attention deficit and an increase in anxiety, without any impairment in spatial learning and any detectable brain damage (magnetic resonance imaging and histological analysis). Post-anoxic rats showed a reduction in the expression of group-I metabotropic glutamate receptors (i.e. mGlu1 and mGlu5 receptors) in the hippocampus and cerebral cortex, whereas expression of the mGlu 2/3 receptors, the NR1 subunit of NMDA receptors, and the GluR1 subunit of alpha-amino-3-hydroxy-5-methylisoxazole-4-propionate (AMPA) receptors was unchanged. mGlu1 and mGlu5 receptor signalling was also impaired in postanoxic rats, as revealed by a reduced efficacy of the agonist (1S,3R)-1-Aminocyclopentane-1,3-dicarboxylic acid (1S,3R-ACPD) to stimulate polyphosphoinositide hydrolysis in hippocampal slices. We conclude that rats subjected to subneurotoxic doses of anoxia during the early post-natal life develop behavioural symptoms that are frequently encountered in the inattentive subtype of the attention deficit hyperactivity disorder, and that group-I mGlu receptors may be involved in the pathophysiology of these symptoms.

Animals↗

Social withdrawal, neophobia, and stereotyped behavior in developing rats exposed to neonatal asphyxia.

Perinatal asphyxia is a concern for public health and may promote subtle neuropsychiatric disorders. Anoxic insults to neonatal rats cause long-lasting neurobehavioral deficits. In the present study, we focussed on changes in emotional behaviors as a consequence of neonatal asphyxia in Wistar rats. Newborn pups (24 h after birth) underwent a single 30-min exposure to a 100% N2 atmosphere (or air). The offspring was tested for a) locomotor and exploratory activity with or without a d-amphetamine challenge (0, 1, or 2 mg/kg) on postnatal day (pnd) 15; b) social interactions and novelty seeking during adolescence; c) levels of the brain-derived neurotrophic factor (BDNF). In the open-field test (pnd 15), N2-exposed pups injected with the high (2 mg/kg) amphetamine dose exhibited reduced levels of locomotor hyperactivity, and a more marked involvement in stereotyped behaviors. Individual differences emerged in the locomotor response to the novelty-seeking test: two subgroups of rats (separated on the basis of the median value) showed either arousal/attraction or avoidance/inhibition in response to free-choice novelty. The N2-exposed group showed a more marked novelty-induced avoidance and inhibition. Time devoted to allogrooming and play-soliciting behaviors was reduced, whereas object exploration was increased. Levels of BDNF were reduced in the striatum of N2-exposed rats, suggesting poorer synaptic performance of dopamine pathways. In conclusion, these findings suggest an increased risk of developing social withdrawal, neophobia and behavioral stereotypies (common symptoms found in schizophrenia and autism) as a consequence of neonatal asphyxia in preterm humans.

Analysis of Variance↗

Epigenetic control of neurobehavioural plasticity: the role of neurotrophins.

Nerve growth factor (NGF) and brain-derived neurotrophic factor (BDNF) are two neurotrophins involved in the differentiation, growth and maintenance of selected peripheral and central populations of neuronal cells, during development and at adulthood. Furthermore, neuronal activity enhances expression and action of these neurotrophins, modifying synaptic transmission and connectivity. Neurotrophin production has been shown to be experience-dependent. In particular, during early developmental phases, experiences such as maternal deprivation or exposure to an enriched environment markedly affect NGF and BDNF levels. At adulthood, psychosocial stress has been shown to markedly alter NGF and BDNF levels, both in plasma and selected brain areas, including the hypothalamus and hippocampus. These results have been extended to humans, showing that NGF levels are enhanced by emotional stress induced by parachute jumping. Overall, these findings suggest a role of neurotrophins as factors mediating both short- and long-term effects of experience on brain structure and function.

Aggression↗

Stress and nerve growth factor: findings in animal models and humans.

Stress is elicited by environmental, social or pathological conditions occurring during the life of animals and humans that determine changes in the nervous, endocrine and immune systems. In the present review, we present data supporting the hypothesis that stress-related events both in animal models and humans are characterized by modifications of endogenous nerve growth factor (NGF) synthesis and/or utilization. Stress inducing alteration in NGF synthesis and/or utilization appears to be more severe during neurogenesis and in early postnatal life. However, NGF endogenously released during stress may promote remodeling of damaged tissues following acute and/or chronic stressful events.

Animals↗

Ultrasonic vocalisation emitted by infant rodents: a tool for assessment of neurobehavioural development.

Ultrasonic vocalisations (USVs) emitted by altricial rodent pups are whistle-like sounds with frequencies between 30 and 90 kHz. These signals play an important communicative role in mother-offspring interaction since they elicit in the dam a prompt response concerning caregiving behaviours. Both physical and social parameters modulate the USV emission in the infant rodent. Recently, a more detailed analysis of the ultrasonic vocalisation pattern, considering the spectrographic structure of sounds has allowed a deeper investigation of this behaviour. In order to investigate neurobehavioural development, the analysis of USVs presents several advantages, mainly: (i) USVs are one of the few responses produced by very young mice that can be quantitatively analysed and elicited by quantifiable stimuli; (ii) USV production follows a clear ontogenetic profile from birth to PND 14-15, thus allowing longitudinal neurobehavioural analysis during very early postnatal ontogeny. The study of this ethologically-ecologically relevant behaviour represent a valid model to evaluate possible alterations in the neurobehavioural development of perinatally treated or genetically modified infant rodents. Furthermore, the role played by several receptor agonists and antagonists in modulating USV rate makes this measure particularly important when investigating the effects of anxiogenic and anxiolytic compounds, and emotional behaviour in general.

Animals↗

Effect of hypergravity on the mouse basal expression of NGF and BDNF in the retina, visual cortex and geniculate nucleus: correlative aspects with NPY immunoreactivity.

We investigated the effect of hypergravitation on Nerve growth factor (NGF) and Brain-derived-neurotrophic factor (BDNF) expression in the visual cortex, geniculate nucleus (GN), and retina of adult male mice. The results showed that altered gravity causes an increase in NGF and BDNF in the visual cortex and GN which resulted to be associated with an up-regulation of cells immunoreactive to neuropeptide Y (NPY) in the visual cortex and GN. We also found a decrease in NGF, BDNF, and NPY in the mouse retina exposed to hypergravity. These findings suggest that alteration in gravitational environment differentially affects local neurotrophic factors and NPY expression. The possible functional significance of these observations is discussed.

Animals↗

Prenatal exposure to anti-HIV drugs: neurobehavioral effects of zidovudine (AZT) + lamivudine (3TC) treatment in mice.

BACKGROUND: The new antiretroviral treatments that combine the zidovudine (AZT) regimen with lamivudine (3TC) appear as a cost-effective alternative to the current AZT monotherapy to prevent mother-to-fetus transmission of the HIV-1 virus. Recent evidence in uninfected children raised concern about the long-term effects of perinatal exposure to AZT and 3TC, especially when used in combination. Animal studies indicated behavioral changes in offspring exposed perinatally to both AZT and 3TC, whereas no animal data are available on the effects of the perinatal exposure to the AZT + 3TC combination on neurodevelopment. METHODS: Pregnant CD-1 mice received p.o. AZT + 3TC (160 and 500 mg/kg, respectively) or vehicle solution (NaCl 0.9%) twice daily from gestational day 10 to delivery. Maternal reproductive endpoints such as pregnancy length, abortion, litter size, sex ratio, and offspring viability were assessed. Pups were scored for different somatic and behavioral endpoints, including sensorimotor development, homing performance on postnatal day (PND) 10, passive-avoidance testing (PND 22-23), locomotor activity (PND 23), and social interaction (PND 35). RESULTS: While no effects were observed on maternal reproductive endpoints, treated pups showed a long-lasting reduction of body weight and a slightly delayed maturation of placing and grasping reflexes and pole grasping. No effects on passive-avoidance or locomotor activity were found. AZT + 3TC-treated mice showed selective alterations in the social interaction test; the treated female offspring also displayed a significant reduction of affiliative interactions. CONCLUSIONS: The combination of AZT and 3TC (1) induced small, but more marked, effects on somatic and sensorimotor development than either of these drugs administered separately; and (2) affected juvenile social behavior.

Animals↗

Prolonged exposure to low doses of ozone: short- and long-term changes in behavioral performance in mice.

Two separate experiments were designed to assess the effects of ozone exposure on outbred CD-1 mice. In the first experiment, adult males were exposed continuously to O3 at 0, 0.3, or 0.6 ppm for 30 days and their behavior was assessed in a 5-min open-field test on exposure days 4 and 19 and on day 3 after the end of the exposure phase. In addition, mice performed a Morris water maze task from exposure day 24 to 28. In the second experiment, adult females were exposed from 30 days prior to the formation of breeding pairs until gestational day 17 to the same doses used in the first experiment. Litters were fostered at birth to untreated dams and neurobehavioral development of the offspring was investigated until adulthood. Specifically, somatic and sensorimotor development [postnatal day (PND) 2-20], homing performance (PND 12), motor activity (PND 21), passive avoidance (PND 22-23), water maze performances (PND 70-74), and response to a nociceptive stimulus (PND 100) were assessed. Results from both experiments confirm that exposure to O3 slightly but selectively affected neurobehavioral performance in rodents. Exposure to O3 did not grossly affect neurobehavioral development, whereas it consistently impaired reversal learning in the Morris water maze test in both prenatally and adult exposed mice. Moreover, longer latency to step-through in the first trial of the passive avoidance test and a decrease in wall rearing in the hot-plate test were recorded in O3 prenatally exposed mice. Except for the first open-field test, altered responses were observed only in animals exposed at the intermediate concentration of the gas. Adaptation and/or onset of compensatory mechanisms might be responsible for the lack of linear dose-response relationships.

Adaptation, Physiological↗

Prenatal AZT or 3TC and mouse development of locomotor activity and hot-plate responding upon administration of the GABA(A) receptor agonist muscimol.

RATIONALE: Zidovudine (AZT) and lamivudine (3TC) are nucleoside analogues administered prenatally in clinical practice, separately or in combination, as antiretroviral drugs to prevent HIV mother-to-child transmission by inhibiting viral reverse transcriptase. In animal studies pre- and/or perinatal exposure to AZT and 3TC induce age- and sex-dependent neurobehavioural alterations in the offspring. OBJECTIVE: Investigation of short- and medium-term effects of in utero exposure to AZT or 3TC on development of the GABAergic system. METHODS: Pregnant CD-1 mice were given orally twice daily AZT (160 mg/kg), 3TC (500 mg/kg) or vehicle solution (NaCl 0.9%) from pregnancy day 10 to delivery. Offspring locomotion and nociceptive sensitivity were examined on postnatal day (pnd) 8, 14, and 28 after administration of two doses of GABAergic agonist muscimol (pnd 8 and 14: 0.05 and 0.2 mg/kg; pnd 28: 0.2 and 1.0 mg/kg). A 30-min locomotor activity test and a 60 s hot-plate test (50+/-1 degrees C) were used. RESULTS: AZT and 3TC treated mice showed a mild increase of locomotor activity after administration of the high dose muscimol on pnd 8. On pnd 14 the low muscimol dose enhanced locomotor activity in vehicle and 3TC, but not in AZT pups, whereas no prenatal treatment effect was evident on pnd 28. AZT increased nociceptive sensitivity at all ages considered. CONCLUSIONS: Prenatal AZT effects on locomotor activity appear clearly detectable after GABAergic challenge and seem to be transient. AZT effects on pain sensitivity did not appear to be dependent on GABA regulated nociceptive mechanisms. Prenatal 3TC exposure had rather limited effects on locomotor activity development, and no effect on nociception.

Animals↗

Psychosocial vs. "physical" stress situations in rodents and humans: role of neurotrophins.

Nerve growth factor (NGF) and brain-derived neurotrophic factor (BDNF) are well-studied polypeptide growth factors involved in the development and maintenance of specific peripheral and central populations of neuronal cells. In addition to its role as a neurotrophic agent, NGF controls very complex functions in vertebrate physiology. A variety of cells outside the nervous system are in fact able to synthesize NGF including epithelial cells, fibroblasts, lymphocytes, and macrophages. NGF target cells have been identified in the nervous, immune, and endocrine systems, suggesting that NGF may operate through multiple paths to ultimately regulate physiological homeostasis and behavioral coping. We used a mouse model of social stress to demonstrate that NGF levels increase both in plasma and in the hypothalamus following intermale aggressive interactions. The investigation has been extended to other species, including humans, to show that labour, lactation, and the anticipation of the first jump with a parachute also result in increased NGF plasma levels and in changes in the distribution of NGF receptors on lymphocytes. BDNF activation is caused by both physical and social stress events. The aim of this review is to (1) outline the current understanding of the roles of NGF and BDNF in stress-related physiological changes in vertebrates, in particular for physical vs. psychological stressors, which may activate both similar and different neurobiological pathways, and (2) summarize recent efforts to derive pharmacological strategies from the increasing body of BDNF and NGF neurobehavioral data.

Animals↗

Response of CD-1 mice to the chemical defence of a common arthropod (Ommatoiulus sabulosus).

In order to set up a novel and ethologically relevant methodology that could be applied to the study of olfactory capabilities in transgenic mice, we analysed the behavioural responses of sexually mature male and female CD-1 mice individually exposed to a striped millipede, Ommatoiulus sabulosus (L.), a very common myriapod species that secretes a repulsive and persistent odour in the presence of a predator. As control, we exposed mice to a larva of the lepidopteran Greater wax moth, Galleria mellonella (L.), which closely resembles the millipede in shape and dimensions but which does not secrete a repulsive odour in defence. We recorded and analysed a wide spectrum of behavioural responses including both those of avoidance and nonavoidance such as attempts to eat the arthropod. Behavioural responses were measured for 10 min upon first exposure to the millipede or wax moth. The procedure was repeated for 3 consecutive days. Upon exposure to a millipede, mice of both sexes showed a dramatic increase in the avoidance behaviour of digging. Moreover, millipedes were repulsive to mice and though they were sniffed frequently and sometimes caught, they were never eaten. In comparison, mice exposed to a wax moth almost always ate it. Sex differences emerged only for locomotion with female appearing to be more active. These results suggest that mice are able to discriminate between ethologically relevant odours and that the behavioural responses they display in this more natural context differ from those observed in response to odours of predators.

Animals↗

NGF expression in the developing rat brain: effects of maternal separation.

A number of studies have shown that mothering style in rodents can produce neuroendocrine, neurochemical and behavioural changes in the adult, although the basic mechanisms initiating this cascade of events still need to be investigated. Long term changes in neuronal function might be due to alterations in the expression of neurotrophins which have been shown to promote neuronal survival, differentiation and function during development, such as Nerve Growth Factor (NGF). NGF is essential for proper development of sympathetic and neural crest-derived sensory neurons of the peripheral nervous system as well as of central cholinergic neurons. In previous studies, using a maternal separation paradigm, we have shown that NGF expression is increased in the dentate gyrus and the hilus of the hippocampus as a result of brief (45 min) maternal separations. In the present study neonatal rats were separated for longer periods of time (up to 3 h) and at different ages during development (9 and 16 days postnatally). Results indicate that the effects of maternal separation on NGF expression are stronger with longer separations and are not restricted to the hippocampal region but can be seen also in other brain areas. Overall these results indicate that external factors, such as the presence/absence of the mother, can modify neurotrophic factor's availability in the brain, thus indicating NGF as a potential player in environmentally-mediated brain plasticity during development.

Animals↗

Neurobehavioural effects of hypergravity conditions in the adult mouse.

To evaluate the behavioural response to a hypergravity condition in CD-1 mice, young adult subjects of both sexes were exposed to 2 g for a single 60 min rotational session. Motion sickness (MS) and ethological-type scoring of different activities were used to evaluate the behavioural response. Nerve growth factor (NGF) and brain derived neurotrophic factor (BDNF) levels were also assessed. Behavioural scores indicated a transient mild sickness associated with hypergravity, with reduction in spontaneous activity. In males kaolin consumption (a MS index) increased following rotation while females consumed more kaolin irrespective of whether they have been rotated or simply exposed to the noise and vibration of the rotational apparatus. In males, hypothalamic NGF levels were markedly increased after rotation while no major changes were observed in central BDNF expression. These results indicate mice may represent a suitable MS model.

Animals↗

Intracerebroventricular administration of brain-derived neurotrophic factor in adult rats affects analgesia and spontaneous behaviour but not memory retention in a Morris Water Maze task.

The present study tested the effects of in vivo administration of brain-derived neurotrophic factor (BDNF) and of its antibody (anti-BDNF) in a Morris Water Maze (MWM) task. Adult male rats were trained for three days in a MWM. At the end of the last training trial, subjects were injected intracerebroventricularly with one of the following: (i) BDNF (24 microg); (ii) anti-BDNF (25 microg); or (iii) vehicle (PBS, injection volume 10 microl). On day 5, subjects were tested for memory retention, pain sensitivity and locomotor behaviour. No differences emerged in the MWM as a function of treatment, even with a reduced number of acquisition trials. Nonetheless, BDNF affected both pain threshold in the hot-plate test, as well as exploratory behaviour in the open field test.

Animals↗