Biomedical subjects

J Mariani

Publications and source records attributed to J Mariani.

At least 73 records · Page 4Linked to original sources

PubMed1997

Increased inferior olivary neuron and cerebellar granule cell numbers in transgenic mice overexpressing the human Bcl-2 gene.

Neuron-target interactions during development are critical for determining the final numbers of neurons in the nervous system. To investigate the role of Purkinje cells and programmed cell death in the regulation of afferent neuron numbers, we have counted olivary neurons and granule cells in two lines of transgenic mice (NSE73a and NSE71) that overexpress a human gene for bcl-2 (Hu-bcl-2) in Purkinje cells and olivary neurons, but not in granule cells. Bcl-2 overexpression in vivo reduces naturally occurring neuronal cell death and cell death following axotomy, target removal, or ischemia. Olivary neuron numbers in NSE73a and NSE71 transgenic mice are significantly increased compared to controls by 28% and 27%, respectively, while granule cell numbers are only increased in NSE73a mice (29% above controls). We have previously shown that Purkinje cell number is increased by 43% in NSE73a transgenics and by 23% in NSE71 transgenics. The ratio of Purkinje cells to olivary neurons is not significantly different between the control and transgenic mice, while the ratio of granule cells to Purkinje cells is significantly decreased in the NSE71 transgenic mice compared to controls and NSE73a transgenics. The increased numbers of olivary neurons suggest that bcl-2 overexpression rescues these neurons from programmed cell death. The increase in granule cell number in only one transgenic line is discussed with respect to hypotheses that Purkinje cells regulate both granule cell progenitor proliferation and the survival of differentiated granule cells.

Animals↗

PubMed1997

Role of the inferior olivary complex in motor skills and motor learning in the adult rat.

The inferior olivary complex of adult rats was chemically destroyed using intraperitoneal injection of 3-acetylpyridine. Animals were submitted to different motor tasks: hanging test, equilibrium test and motor co-ordination test. The different scores show that 3-acetylpyridine-treated rats had motor co-ordination and static equilibrium deficiencies, whereas their rod suspension capabilities were intact. Animals were also trained on an unrotated rod or on a rod rotating at 5, 10 or 20 r.p.m. 3-Acetylpyridine-treated rats were able to maintain their equilibrium on the unrotated rod and at 5 r.p.m. Moreover, after motor training at 5 r.p.m., rats were able to improve their motor skills and reached the same score as controls. Despite their good motor skills, animals were unable to maintain their equilibrium when rotated at 10 and 20 r.p.m. These results suggest that the inferior olivary complex is needed for motor learning involving the temporal organization of movement.

Age Factors↗

PubMed1997

Synaptic beta-amyloid precursor proteins increase with learning capacity in rats.

The precursor proteins of Alzheimer's disease beta-amyloid peptide, the beta-amyloid precursor protein isoforms, comprise a family of neuronal proteins with synaptic localization whose physiological roles in brain are poorly understood. One possible role for synaptic proteins is involvement in neuronal plasticity. After exposure to an enriched environment compared to impoverished conditions, rats exhibited superior cognitive capacity. Up to approximately four-fold increased overall levels of beta-amyloid precursor proteins were found in cortical/subcortical tissue of the enriched animals displaying significantly more synapses immunoreactive for the different beta-amyloid precursor protein isoforms (beta-amyloid precursor protein695- and beta-amyloid precursor protein751/770) in hippocampus and adjacent occipital cortex. This correlation thus provides in vivo evidence for an association of beta-amyloid precursor proteins with plastic changes induced by complex environment with consequences for cognitive functions and suggests that impaired beta-amyloid precursor protein metabolism at synapses might contribute to brain dysfunction in Alzheimer's disease.

Amyloid beta-Protein Precursor↗

PubMed1997

Delayed spontaneous alternation in intact and cerebellectomized control and lurcher mutant mice: differential role of cerebellar cortex and deep cerebellar nuclei.

Lurcher mutant (+/Lc) mice exhibit a massive loss of neurons in the cerebellar cortex and in the inferior olivary nucleus while deep cerebellar nuclei are essentially intact. To discriminate the respective participation of the cerebellar cortex and deep structures in learning and memory, the authors subjected 3- to 6-month-old +/Lc mice to a delayed spontaneous alternation task to test their working and long-term spatial memories. Results show that wild type (+/+) mice alternated above chance even after a 1-hr delay between the forced and choice trials, whereas in +/Lc mice, long-term memory was impaired. Cerebellectomized +/+ mice behave as +/Lc mice (working memory was preserved but long-term memory was not), whereas in the cerebellectomized +/Lc mice, both working and long-term memories were altered. These results are discussed in terms of relationships between the cerebellum and the hippocampus.

Animals↗

PubMed1997

Effect of cerebellar granule cell depletion on learning of the equilibrium behaviour: study in postnatally X-irradiated rats.

To assess the role of the mossy fibre-granule cell pathway in learning, the cerebellum of young DA/HAN strain rats was irradiated to make the cortex completely or partially agranular. The X-rays were delivered according to two different schedules, between 5-14 postnatal days (early group) and between 10-14 postnatal days (late group). Histological controls at 35 days showed a mean loss of granule cells of 96 +/- 1% in the early group and of 61 +/- 3% in the late group. The irradiated animals were subjected, from day 23 to day 35, to daily sensorimotor training on a rotorod. The scores and the strategy used (walking or hanging) by the rats were noted. The results demonstrate that a partial loss of granule cells due to a late X-irradiation schedule induced mild motor disabilities but no learning deficit, the only problem being difficulty in elaborating rapidly an efficient strategy to solve a novel problem. A sub-total loss of the granule cells, due to an early X-irradiation schedule, induced gross motor disabilities and the animals used hanging > 90% of the time. Due to the discrepancy between the learning abilities, which were preserved at least in part, and the gross motor impairments, the animals elaborated a novel strategy (jumping from the beam), allowing them to escape the experimental situation. This avoidance behaviour may be due to a decrease of anxiety, a lack of behavioural inhibition and/or attentional deficits that have been already observed in several other examples of cerebellar abnormalities.

Aging↗

PubMed1997

Enhanced endocrine response to novel environment stress and endotoxin in Lurcher mutant mice.

Lurcher mutant mice which are mainly known for their cerebellar degeneration, also display a hyperinducibility of proinflammatory cytokines, such as interleukin-1alpha and beta (IL-1) and tumor necrosis factor alpha (TNF-alpha), in peripheral macrophages. To assess whether this increased responsiveness to inflammatory stimuli is accompanied by a higher pituitary-adrenal response, we compared the adrenocorticotropic hormone (ACTH) and corticosterone response of Lc and wild-type mice to intraperitoneal (i.p.) administration of a cytokine inducer, lipopolysaccharide (LPS). Lurcher mice display resting levels of ACTH and corticosterone similar to those of wild-type mice. LPS (1.25 microg/g) induces a corticosterone surge 2-fold higher in Lurcher than in wild-type mice. By contrast, the response to IL-1alpha (10 ng/g, i.p.) is similar in both genotypes, suggesting that a differential reactivity of the hypothalamo-pituitary adrenal axis to IL-1 does not account for the higher reactivity of Lurcher mice to LPS. To test whether the increased responsiveness of the pituitary-adrenal axis of Lurcher mice generalizes accross stressors, mice were exposed to a novel environment. This condition also induced a surge of ACTH and corticosterone 3.5- and 2-fold higher in Lurcher than in wild-type mice. Prior blockade of IL-1 receptors by injection of IL-1 receptor antagonist (10 microg/g, i.p.) failed to block the response to LPS injection and exposure to novelty. In contrast, immunoneutralization of hypothalamic corticotropin-releasing hormone (CRH) significantly attenuated the ACTH surge and abrogated the difference between Lurcher and wild-type mice in their responses to a novel environment, suggesting that hypothalamic CRH neurons are involved in this excessive response.

Adrenocorticotropic Hormone↗

PubMed1997

[Caenorhabditis elegans and neuronal death in mammals].

The development of the nervous system implies not only the generation of neurons, but also their death. This neuronal death can occur through several mechanisms, one of them being apoptosis. This type of cell death seems to be also implicated in some neurodegenerative diseases. This study of the nematode Caenorhabditis elegans has led to the discovery of several genes controlling apoptosis in neurons. Two of them, the pro-apoptotic ced3 and the anti-apoptotic ced9, have mammalian homologs. The mammalian homologs to Ced9 form the Bcl-2 family and can be either pro-apoptotic or anti-apoptotic. Some of them, Bcl-x, and Bax have been shown to be involved in neuronal death during development in some pathological situations. The first mammalian homolog of Ced3 to be described was the Interleukin-1b Converting Enzymes (ICE). Since then, many other homologs of the proteases Ced3 and ICE have been discovered constituting the Caspases family. These Cysteinyl Aspartate Specific Proteases are pro-apoptotic in many different systems. Several studies using viral or peptidic inhibitors of the Caspases have demonstrated their role in neuronal death in vitro. In vivo, CPP32, a member of the Caspases family, has been shown to be clearly involved in the development of the nervous system. Finally, the analysis of apoptosis in Caenorhabditis elegans has led to the discovery of two families of genes involved in the cascade of events inducing neuronal death in mammals. Indeed, the Caspases seem to be controlled by the Bcl-2 family, as Ced3 is by Ced9.

Animals↗

PubMed1996

The numerical matching of source and target populations in the CNS: the inferior olive to Purkinje cell projection.

During a defined critical period of development, if the target of a neuronal population is removed, there is a massive decrease in the number of neurons that survive into adulthood. Previous studies have found that source neuron number is a strictly linear function of target size. The current work extends these observations to the inferior olive-->Purkinje cell projection. Three distinct model systems have been used: (i) lurcher<-->wild-type aggregation chimeras, (ii) staggerer<-->wild-type chimeras and (iii) naturally occurring polymorphisms in Purkinje cell number found in different inbred mouse strains. Total neuron numbers were counted in the inferior olive and plotted as a function of the number of Purkinje cells in the contralateral cerebellar cortex. In lurcher mutants and chimeras, the relationship between these values is well described by a straight line. This suggests that, like the granule-->Purkinje cell circuit, the olive-->Purkinje cell circuit uses a linear algorithm to achieve a numerical balance. The results from the two other model systems were not as clear cut. In the staggerer chimeras, we found only a rough correlation between neuron and target numbers and in the inbred strains there was no discernible relationship at all. These findings indicate that in the final analysis, there are multiple factors involved in the determination of the number of olive cells surviving into adulthood. The potential contribution of sustaining collaterals and afferent inputs is discussed as well as the possible existence of different subcircuits of olivocerebellar connections, each with its own numerical matching function.

Animals↗

PubMed1996

Increased cerebellar Purkinje cell numbers in mice overexpressing a human bcl-2 transgene.

The Purkinje cell is a primary organizer in the development of the cerebellum. Purkinje cells may provide positional information cues that regulate afferent innervation, and Purkinje cell target size controls the adult number of afferent olivary neurons and granule cells. While Purkinje cells are necessary for the survival of olivary neurons and granule cells during periods of programmed cell death, little is known about the survival requirements of Purkinje cells in vivo. To determine if Purkinje cells are subject to programmed cell death during development we have analyzed Purkinje cell numbers in two lines of transgenic mice that overexpress a human gene for bcl-2 (Hu-bcl-2). Bcl-2 is a protooncogene that inhibits apoptosis in many cell types. Overexpression of bcl-2 in vitro and in vivo rescues neurons from trophic factor deprivation or naturally occurring cell death. In the mice analyzed in this study, transgene expression is driven by the neuron-specific enolase promoter that is first expressed embryonically in most regions of the brain in one line and postnatally in the second line. We have counted Purkinje cells in three adult control mice, five early overexpressing transgenics, and three late expressing transgenics. The number of Purkinje cells in the Hu-bcl-2 transgenic mice is significantly increased above control numbers, with an increase of 43% in the embryonically overexpressing line and an increase of 27% in the postnatally overexpressing line. Because bcl-2 overexpression has been shown to rescue other neurons from programmed cell death, the increase in Purkinje cell numbers in overexpressing bcl-2 transgenics suggests that Purkinje cells undergo a period of cell death during normal development.

Animals↗

PubMed1996

Over-expression of interleukin-1 beta-converting enzyme mRNA in staggerer cerebellum.

Interleukin-1 beta-converting enzyme (ICE), involved in the maturation process of interleukin-1 beta (IL-1 beta, is a homologue of ced-3, a protease required for programmed cell death in Caenorhabditis elegans. Over-expression of ICE induces programmed cell death in certain mammalian cell types, whereas in neurones of the central nervous system such a role has yet to be established. We show that ICE mRNA expression is increased 4-fold in the cerebellum of homozygous staggerer mice, where IL-1 beta mRNA is overexpressed and programmed neuronal cell death occurs. Intraperitoneal injection of endotoxin (LPS) induced a strong phasic increase in IL mRNA levels in the cerebellum, whereas the ICE mRNA level increased only moderately. Involvement of ICE in neuronal cell death in the cerebellum of staggerer mice is suspected.

Animals↗

PubMed1996

Cerebellar granule cell differentiation in mutant and X-irradiated rodents revealed by the neural adhesion molecule TAG-1.

In the external granular layer of the cerebellum, the granule cell precursors express the transient axonal glycoprotein TAG-1, a molecule involved in adhesion and neurite outgrowth. Granule cells express TAG-1 transiently, just as they extend neurites before migrating over the radial glia. The present study aims to investigate whether the expression pattern of TAG-1 is altered when granule cells develop abnormally. We studied in vivo models in which Purkinje and/or granule cell defects occur during postnatal development. These include the cerebellar mutant mice staggerer and lurcher as well as rats irradiated during postnatal development. Neither alterations in Purkinje cell differentiation nor the related granule cell loss in the mouse mutants impairs the ability of the surviving granule cell precursors to express TAG-1. Also, early granule cell loss in the X-irradiated rats do not disturb the TAG-1 expression phase in the patches of surviving granule cell precursors. Ectopic granule cells found in the adult cerebellum of X-irradiated rats do not bear the molecule, although they are located in the most superficial part of the molecular layer, occupied by the immunopositive cells a few days earlier. Thus, TAG-1 marks a very precise stage of granule cell differentiation, and the inward migration process itself is not required for the cessation of the expression. We postulate that TAG-1 may be involved in local differentiation steps restricted to the deep external granular layer such as parallel migratory routes or synchrony of axonal growth.

Animals↗

PubMed1996

Transient synaptic redundancy in the developing cerebellum and isostatic random stacking of hard spheres.

We propose an automaton for the simulation of the distribution of the number of climbing fibers (CF) making synapses on each Purkinje cell (PC) at the maximum of the synaptic redundancy that exists transiently in the newborn cerebellum. This automaton is based on the hypothesis that the synaptic maximum is limited by topological constraints and can be described by an isostatic random stacking of hard spheres. There is convincing agreement between the simulated distribution of the number of CF axons per Purkinje cell and the distribution experimentally obtained by electrophysiological techniques.

Animals↗

PubMed1996

Gender effect on Purkinje cell loss in the cerebellum of the heterozygous reeler mouse.

Homozygous mutant mice such as staggerer (sg/sg) or reeler (rl/rl) exhibit a marked ataxia associated with an atrophic cerebellum during the first postnatal weeks and a reduced number of Purkinje cells, the deficit reaching about 75% in sg/sg and 50% in rl/rl as compared to age- and sex-matched mice from the same strain background. These two mutations are classically viewed as recessive, but we have recently shown that heterozygous staggerer (+/sg) mice exhibit a progressive and age-related loss of Purkinje cells between 3 and 12 months of age, despite their apparent clinical normality (Shojaeian-Zanjani et al., 1992). In the present study, we have investigated whether a similar cell loss exists in the cerebellum of heterozygous +/rl mice. The number of Purkinje cells was counted in serial parasagittal sections of the cerebellum of +/rl and their +/+ littermates at 3, 16 and 26 months of age. Our results reveal a 16% deficit in the number of Purkinje cells in 3-month-old +/rl and a 24% one in 16-month-old animals: surprisingly this deficit is only present in the +/rl males, while the females are spared. These results suggest that the reeler gene (D'Arcangelo et al., 1995) exerts its effect on Purkinje cell number in a gender-specific fashion in heterozygous mutant mice.

Aging↗

PubMed1995

Motor behavior of heterozygous staggerer mutant (+/sg) versus normal (+/+) mice during aging.

Three- to 24-month-old heterozygous staggerer (+/sg) and control (+/+) C57B16 mice were subjected to a motor test on a rota rod rotating at 30 or 40 revolutions per minute. The scores were evaluated by the time during which they maintained their equilibrium without falling down. Although the scores of both +/sg and +/+ animals decreased with age, the scores of +/sg mice were constantly lower at 3, 6 and 12 months and this difference was already significant at 3 months, i.e., before the 30% loss of Purkinje cells, granule cells and inferior olivary neurons which occurs between 3 months and 1 year in the mutant. At 18 months and beyond, scores no longer differed in both groups. These results show that there is no strict correlation between neuronal death in the cerebellar cortex and motor behavior on the rota rod. However, the difficulties in maintaining their equilibrium on the rota rod observed in +/sg mice as young as 3 months, indicate a deficit in accurate motor control which could be due to subtle structural or neurochemical disorders that probably precede neuronal death. Therefore, in the heterozygous staggerer, behavioral motor disturbance is a sign of cerebellar dysfunction which appears earlier than alterations in neuronal number.

Aging↗

PubMed1995

Abnormal ipsilateral functional vibrissae projection onto Purkinje cells multiply innervated by climbing fibers in the rat.

We have previously shown that synapse elimination occurring in the climbing fiber (CF)-Purkinje cell (PC) relationships during normal postnatal development is likely involved in the refinement of vibrissae projections onto the cerebellar cortex. In normal adult rats, CF-mediated vibrissae projections onto cerebellar Purkinje cells of the vermis of lobule VII are strictly contralateral and located in a narrow microzone whereas they are widely distributed in rats whose PCs remained multiply innervated by CFs due to postnatal irradiation. Given the proximity of this microzone to the midline, the question arose as to whether this synapse elimination process could participate in the segregation of ipsilateral and contralateral projections. In the present study, we compared the topographical map of the ipsilateral and contralateral CF-mediated projections of the third row of vibrissae onto the vermal PCs of lobule VII in adult normal rats and in polyinnervated rats. Using intracellular electrophysiological recordings, we examined the responsiveness of PCs to mechanical stimulation of vibrissae, and positioned responsive cells on an averaged planar map of lobule VII. In normal rats no ipsilateral responses were found, while in irradiated rats ipsilateral responses were distributed evenly from the midline to 700 microns apart. These results suggest that synapse elimination participates in the segregation of ipsi and contralateral mystacial inputs to the vermis.

Animals↗

PubMed1995

Differential roles of cerebellar cortex and deep cerebellar nuclei in the learning of the equilibrium behavior: studies in intact and cerebellectomized lurcher mutant mice.

Three- to 6-month-old lurcher mutant mice (+/lc), which exhibit a massive loss of neurons in the cerebellar cortex and in the inferior olivary nucleus but whose deep cerebellar nuclei are essentially intact, were trained daily, for 9 days, to maintain their equilibrium upon a rota rod rotating at 20 or 30 revolutions per minute (rpm). Their scores were measured and their behavior upon the rotating rod quantified in comparison to those of matched control (+/+) mice. Lurcher mice were able to learn to maintain their equilibrium efficiently when rotated at 20 rpm but were not when rotated at 30 rpm. After cerebellectomy, the equilibrium capabilities of the animals were much altered, especially in +/lc. These results show that the deep cerebellar nuclei are sufficient for motor learning, provided the task is not too difficult (20 rpm), but that the cerebellar cortex is required when the task is more difficult (30 rpm). Therefore, it can be concluded that the adaptive motor capabilities of lurcher mice are less developed than those of control animals.

Animals↗

PubMed1995

Inflammatory processes induce beta-amyloid precursor protein changes in mouse brain.

In Alzheimer disease, a combination of genetic predisposition and environmental factors may contribute to changes in beta-amyloid precursor protein (APP) expression, beta-amyloid peptide deposition, and neuronal loss. Factors such as head injury or acute infection that trigger inflammatory processes may play a crucial role in development of the disease. In the present in vivo study, we showed that, in mouse brain, peripheral stimulation with lipopolysaccharide (LPS) induced a transient increase in the inflammatory cytokine mRNAs (interleukin 1 beta and interleukin 6), followed by changes in expression of APP isoforms in the cerebellum but not in the cerebral cortex. These changes consisted of a decrease in the APP-695 and an increase in the Kunitz protease inhibitor-bearing isoforms (KPI-APP). In the cerebellum of the staggerer mouse mutant, where a severe loss of Purkinje and granule cells occurs, basal mRNA levels of these interleukins were elevated and an increase in the KPI-APP/APP-695 ratio compared to wild-type mice was observed. These abnormalities were further accentuated by LPS stimulation. This study shows that acute and chronic inflammatory processes play an important role in changes in APP expression possibly associated with neurodegeneration.

Amyloid beta-Protein Precursor↗

PubMed1995

5'-nucleotidase activity as a synaptic marker of parasagittal compartmentation in the mouse cerebellum.

In the molecular layer of the mouse cerebellum, the histochemical activity of the adenosine-producing ectoenzyme 5'-nucleotidase discloses a parasagittal pattern of alternating enzyme-rich and enzyme-poor bands. In the rat, 5'-nucleotidase activity transiently labels cerebellar synapses during postnatal development and shifts later on towards an exclusive glial location in the molecular layer. We therefore asked whether different ultrastructural expression of 5'-nucleotidase would account for the light microscopic pattern seen in the adult mouse cerebellum. Using an enzyme cytochemical method, we localized 5'-nucleotidase activity on the glial cells and at the main types of asymmetrical synapses in the developing and mature cerebellum of the mouse. The percentage of labelled synapses increased until adulthood within the 5'-nucleotidase-positive bands. Here, the vast majority (86%) of the synapses were labelled against only 27% within the negative bands in the adult. Thus, 5'-nucleotidase appears as a marker of glia and of Purkinje cell synapses across cerebellar compartments. Changes in purinergic neuromodulation and/or cell adhesion mediated by 5'-nucleotidase across bands might participate in the functional differentiation of the cerebellar parasagittal subsets.

5'-Nucleotidase↗