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Biomedical subjects

A Parent

Publications and source records attributed to A Parent.

At least 19 recordsLinked to original sources
PubMed2006

Relationship between axonal collateralization and neuronal degeneration in basal ganglia.

In this paper we evaluate the hypothesis of a possible link between the degree of axonal collateralization of neurons located within the different components of basal ganglia and the vulnerability of these neurons to neurodegenerative or neurotoxic events. Our results stemmed from single-cell labeling experiments in rodents and primates, immunohistochemical study of the dopaminergic nigrostriatal pathway in parkinsonian monkeys, and immunocytological analysis of the human striatum in normal individuals and in patients with Huntington's disease. Our results indicate that projection neurons within virtually all basal ganglia components are endowed with a widespread and highly collateralized axon that yields a fixed number of terminals. Such a high degree of axonal collateralization allows exquisitely precise interactions between the various basal ganglia nuclei. However, the maintenance of this unique morphological trait implies high-energy consumption and renders basal ganglia neurons highly vulnerable to neurodegenerative, metabolic or neurotoxic insults.

Animals↗
PubMed2003

Marrow stem cell potential within a continuum.

On the basis of our studies of the fluctuation of the hematopoietic stem cell phenotype with cell cycle trnsit, we hypothesize that the ability of marrow stem cells to convert to nonhematopoietic cells will also vary at different points in the cell cycle. The new biology of stem cells has an impact on many fields including developmental biology and stem cell biology and the clinical potential is enormous.

Animals↗
PubMed2001

Early environmental regulation of hippocampal glucocorticoid receptor gene expression: characterization of intracellular mediators and potential genomic target sites.

Environmental conditions in early life permanently alter the development of glucocorticoid receptor gene expression in the hippocampus and hypothalamic-pituitary-adrenal responses to acute or chronic stress. In part, these effects can involve an activation of ascending serotonergic pathways and subsequent changes in the expression of transcription factors that might drive glucocorticoid receptor expression in the hippocampus. This paper summarizes the evidence in favor of these pathways as well as recent studies describing regulatory targets on the promoter region of the rat hippocampal glucocorticoid receptor gene.

Animals↗
PubMed2001

Two types of projection neurons in the internal pallidum of primates: single-axon tracing and three-dimensional reconstruction.

The axonal projections of the internal pallidum (GPi) in cynomolgus monkeys (Macaca fascicularis) were studied by labeling small pools of neurons with biotinylated dextran amine. Fifty-two axons were reconstructed entirely from serial sections with a camera lucida. Two types of projection neurons were identified in the GPi on the basis of their target sites. The abundant and centrally located type I neurons gave rise to a long axonal branch that descended directly to the pedunculopontine tegmental nucleus, where it arborized discretely. Other branches ascended to the thalamus and broke into 10-15 thinner collaterals that ran through most of the ventral anterior nucleus, where they terminated as typical plexuses. About half of these axons gave rise to collaterals that arborized in both components of the centre médian/parafascicular thalamic complex. The less numerous and peripherally located type II neurons had an axon that climbed the rostral thalamic pole, coursed along the stria medullaris, and arborized profusely within the lateral habenular nucleus, which stood out as the most densely innervated pallidal target. Some type II axons provided collaterals to the anterior thalamic nuclei. A small proportion of axons of both types had branches that crossed the midline and terminated in contralateral GPi target structures. Three-dimensional reconstruction showed that type I axons arborized principally along the sagittal plane. These data reveal that GPi neurons of type I act through a widely distributed axonal network upon thalamic and brainstem premotor neurons, whereas type II neurons act in a much more focused manner upon lateral habenular neurons.

Action Potentials↗
PubMed2001

The nigrostriatal pathway in the rat: A single-axon study of the relationship between dorsal and ventral tier nigral neurons and the striosome/matrix striatal compartments.

Axons from dorsal/ventral tiers of substantia nigra pars compacta (SNc), ventral tegmental area (VTA), and retrorubral field (RRF) were traced after injecting their cell body with biotinylated dextran amine. Fifty-three single axons were reconstructed from serial sagittal sections with a camera lucida, and mu-opiate receptor immunostaining served to differentiate the striosome/matrix striatal compartments. Most dorsal tier SNc axons terminate within the matrix of the dorsal striatum, but their patterns of arborization vary markedly; some axons innervate one specific matriceal area, whereas others arborize in multiple discontinuous loci. Some dorsal tier SNc axons also project to both striosomes and matrix. Other dorsal tier SNc axons, as well as VTA axons, innervate the ventral striatum and send collaterals to striosomes lying ventrally in the dorsal striatum or to the ventral sector of the subcallosal streak (SS). Ventral tier SNc axons arborize principally in striosomes, but some ramify in both compartments or in striosomes and the SS. Ventral tier neurons that form deep clusters in substantia nigra pars reticulata innervate principally the matrix and the SS. The amygdala and ventral pallidum receive secondary collaterals from striatal axons of dorsal/ventral tier neurons or RRF neurons. The subthalamic nucleus receives collaterals from striatal axons of SNc clustered neurons, whereas the globus pallidus gets collaterals from striatal axons of dorsal/ventral tier SNc neurons. These findings reveal that the nigrostriatal pathway is composed of several neuronal subsystems, each endowed with a widely distributed axonal arborization that allows them to exert a multifaceted influence on striatal and/or extrastriatal structures.

Animals↗
PubMed2001

Parkin immunoreactivity in the brain of human and non-human primates: an immunohistochemical analysis in normal conditions and in Parkinsonian syndromes.

The etiology of Parkinson's disease is unknown, but the gene involved in an autosomic recessive form of the disease with early onset has recently been identified. It codes for a protein with an unknown function called parkin. In the present study we produced a specific polyclonal antiserum against human parkin. Immunohistochemical analysis showed that parkin is expressed in neuronal perikarya and processes but also in glial and blood vessels in the primate brain (human and monkey). Electron microscopy indicated that parkin immunoreactivity is mostly located in large cytoplasmic vesicles and at the level of the endoplasmic reticulum. Parkin was expressed heterogeneously in various structures of the brain. It was detectable in the dopaminergic systems at the level of the perikarya in the mesencephalon but also in the striatum. However, parkin was also expressed by numerous nondopaminergic neurons. The staining intensity of parkin was particularly high in the hippocampal formation, the pallidal complex, the red nucleus, and the cerebellum. Comparison of control subjects with patients with Parkinson's disease and control animals with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-intoxicated animals revealed a loss of parkin-immunoreactive neurons only in the substantia nigra pars compacta. Furthermore, the surviving dopaminergic neurons in the parkinsonian state continued to express parkin at a level similar to that observed in the control situation. These data indicate that parkin is a widely expressed protein. Thus, the degeneration of dopaminergic neurons in familial cases of Parkinson's disease with autosomal recessive transmission cannot be explained solely in terms of an alteration of this protein.

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine↗
PubMed2001

A re-evaluation of the current model of the basal ganglia.

The current model of basal ganglia organization has been developed progressively over the last two decades in the light of key observations made at both experimental and clinical levels. This model has been highly successful in that it has stimulated a large amount of research in the field. However, several experimental and clinical findings that are at odds with the model have accumulated during the last decade. This paper reviews some of our own single-axon tracing studies in primates, which call for a re-evaluation of the current basal ganglia model.

Journal Article↗
PubMed2000

Axonal branching pattern of neurons of the subthalamic nucleus in primates.

Axonal projections arising from the subthalamic nucleus (STN) in cynomolgus monkeys (Macaca fascicularis) were traced after labeling small pools (5-15 cells) of neurons with biotinylated dextran amine. Seventy-five single axons were reconstructed from serial sagittal sections with a camera lucida. Most of the STN labeled cells displayed five to eight long, sparsely spined dendrites that arborized mostly along the main axis of the nucleus. Based on their axonal targets, five distinct types of STN projection neurons have been identified: 1) neurons projecting to the substantia nigra pars reticulata (SNr), the internal (GPi) and external (GPe) segments of the globus pallidus (21.3%); 2) neurons targeting SNr and GPe (2. 7%); 3) neurons projecting to GPi and GPe (48%); 4) neurons targeting GPe only (10.7 %); and 5) neurons with axons that coursed toward the sriatum, but whose terminal arborization could not be visualized in detail (17.3%). Axons of the first two types bifurcated into rostral subthalamopallidal and caudal pallidonigral branches. However, the majority of STN axons had only a single branch that coursed rostrally toward the pallidum and striatum. These results reveal that, in contrast to current beliefs, the primate STN is not a monolithic entity. This nucleus harbors several subtypes of projection neurons, each endowed with a highly patterned set of collaterals. This organization allows STN neurons to exert a multifarious effect not only on the GPe, with which the STN is reciprocally connected, but also on the two major output structures of the basal ganglia, the SNr and the GPi.

Animals↗
PubMed2000

Striatal interneurons expressing calretinin, parvalbumin or NADPH-diaphorase: a comparative study in the rat, monkey and human.

The present study is aimed at evaluating the relative number and comparing the pattern of distribution of interneurons containing calretinin (CR), parvalbumin (PV) or NADPH-d in the striatum of rats, squirrel monkeys and humans. A series of adjacent coronal sections taken at three comparable rostrocaudal levels in the three species were treated to reveal the three neuronal markers and the density of each type of chemospecific interneurons was analyzed with a computerized image analysis system. In primates, the most abundant interneurons were those expressing CR. The ratio of CR+/PV+ neurons was approximately 2-3:1 compared to a ratio of 3-4:1 for CR+/NADPH-d+ neurons. In contrast, the most frequently encountered interneurons in the rat striatum were those expressing PV. In rodents, all three interneurons were more abundant rostrally than caudally, but CR+ neurons displayed a particularly striking rostrocaudal decreasing gradient. In monkeys and humans, the three striatal interneurons were distributed rather uniformly rostrocaudally, but CR+ and PV+ interneurons were significantly more numerous in the caudate nucleus than in the putamen in humans. In monkeys, only PV+ neurons were more abundant in the caudate nucleus than in putamen. Overall, the density of the three striatal interneurons was much higher in monkeys than in rats and humans. These results reveal important species differences in respect to the relative density and pattern of distribution of striatal interneurons. These findings should be taken into account when evaluating the effect of neurodegenerative processes on cell densities in the human striatum or when studying animal models of the such diseases.

Animals↗
PubMed2000

Single-axon tracing study of neurons of the external segment of the globus pallidus in primate.

Axonal projections arising from the external segment of the globus pallidus (GPe) in cynomolgus monkeys (Macaca fascicularis) were mapped after labeling small pools (5-15 cells) of neurons with biotinylated dextran amine. Seventy-six single axons were reconstructed from serial sagittal sections with a camera lucida. The majority of labeled GPe cells displayed long, aspiny, and poorly branched dendrites that arborized mostly along the sagittal plane, whereas others showed dendrites radiating in all directions. Numerous GPe axons emitted short, intranuclear collaterals that arborized close to their parent cell body. Based on their axonal targets, four distinct types of GPe projection neurons have been identified: 1) neurons that project to the internal segment of the globus pallidus (GPi), the subthalamic nucleus (STN), and the substantia nigra, pars reticulata (SNr; 13.2%); 2) neurons that target the GPi and the STN (18.4%); 3) neurons that project to the STN and the SNr (52.6%); and 4) neurons that target the striatum (15.8%). Labeled GPe axons displayed large varicosities that often were closely apposed to the somata and proximal dendrites of STN, GPi, and SNr neurons. At striatal levels, however, GPe axons displayed small axonal varicosities that did not form perineuronal nets. These results suggest that the GPe is an important integrative locus in primate basal ganglia. This nucleus harbors several subtypes of projection neurons that are endowed with a highly patterned set of collaterals. This organization allows single GPe neurons to exert a multifarious effect not only on the STN, which is the claimed GPe target, but also on the two major output structures of the basal ganglia, the SNr and the GPi.

Animals↗
PubMed2000

Mechanism of damnacanthal-induced [Ca(2+)](i) elevation in human dermal fibroblasts.

Damnacanthal is a potent and selective inhibitor of p56(lck) tyrosine kinase in a variety of tissues. We have found, however, using the Ca(2+) microfluorimetry technique, that damnacanthal releases intracellular Ca(2+) stores and promotes Ca(2+) entry in human dermal fibroblasts. The effect of damnacanthal on the peak [Ca(2+)](i) values and the latent time to the peak was concentration-dependent. Damnacanthal releases Ca(2+) from thapsigargin-sensitive Ca(2+) stores, and the Ca(2+) stores responding to damnacanthal were overlapped with those of bradykinin. Damnacanthal-induced Ca(2+) entry was mediated by voltage-dependent and voltage-independent Ca(2+) channels. This effect of damnacanthal on intracellular Ca(2+) mobilization was also observed in cultured bovine coronary endothelial cells but not demonstrated in freshly isolated rat basilar smooth muscle cells. Our study suggests that damnacanthal increases intracellular Ca(2+) by releasing Ca(2+) from internal stores and promoting Ca(2+) entry. The relationship between the actions of damnacanthal on tyrosine kinase and intracellular Ca(2+) requires further investigation.

Animals↗
PubMed2000

Enhanced synaptic potentiation in transgenic mice expressing presenilin 1 familial Alzheimer's disease mutation is normalized with a benzodiazepine.

Mutations in presenilin 1 (PS1) are the most common causes of familial Alzheimer's disease (FAD). We examined synaptic physiology in hippocampal brain slices of transgenic mice expressing the FAD-linked PS1 deletion of exon 9 variant. Basal excitatory transmission and paired-pulse facilitation in PS1 mutant mice were unchanged. Short- and long-term potentiation of excitatory transmission following high-frequency stimulation were greater in transgenic mice expressing mutant PS1. Mutants had enhanced synaptic inhibition, which may be a compensatory change offsetting an abnormally sensitized plasticity of excitatory transmission. Increasing inhibitory transmission in mutant animals even more with a benzodiazepine reverted synaptic potentiation to the levels of controls. These results support the potential use of benzodiazepines in the treatment of familial Alzheimer's disease.

Alzheimer Disease↗
PubMed2000

Hemolysate activates P21RAS in rabbit basilar artery.

Cerebral vasospasm is the major factor of mortality and morbidity in the patients who have an aneurysmal subarachnoid hemorrhage (SAH). Erythrocyte lysate (hemolysate), oxyhemoglobin (OxyHb), and bloody cerebrospinal fluid (CSF) are the causative agents for vasospasm. However, the signal transduction pathways for the action of these spasmogens are not clear. In this study, we examined the possible effect of these spasmogens on the p21Ras protein, an important factor in the signal cascade, in rabbit basilar artery. Hemolysate enhanced p21Ras precipitation over a 7-day period. The initial increase of p21Ras precipitation occurred after the tissues were incubated for 2 days with hemolysate. The peak effect of hemolysate, which was markedly increased compared with control (P<0.05, ANOVA), was observed on day 3. OxyHb and blood CSF, in contrast, failed to produce consistent or marked changes in p21Ras precipitation. p21Ras inhibitors FTPase inhibitor 1 and manumycin abolished hemolysate-induced enhancement of p21Ras immunoprecipitation. Genistein, a tyrosine kinase inhibitor, failed to reduce the effect of hemolysate on p21Ras. We concluded that hemolysate activates p21Ras in the rabbit basilar artery.

Animals↗
PubMed2000

Chemical anatomy of striatal interneurons in normal individuals and in patients with Huntington's disease.

This paper reviews the major anatomical and chemical features of the various types of interneurons in the human striatum, as detected by immunostaining procedures applied to postmortem tissue from normal individuals and patients with Huntington's disease (HD). The human striatum harbors a highly pleomorphic population of aspiny interneurons that stain for either a calcium-binding protein (calretinin, parvalbumin or calbindin D-28k), choline acetyltransferase (ChAT) or NADPH-diaphorase, or various combinations thereof. Neurons that express calretinin (CR), including multitudinous medium and a smaller number of large neurons, are by far the most abundant interneurons in the human striatum. The medium CR+ neurons do not colocalize with any of the known chemical markers of striatal neurons, except perhaps GABA, and are selectively spared in HD. Most large CR+ interneurons display ChAT immunoreactivity and also express substance P receptors. The medium and large CR+ neurons are enriched with glutamate receptor subunit GluR2 and GluR4, respectively. This difference in AMPA GluR subunit expression may account for the relative resistance of medium CR+ neurons to glutamate-mediated excitotoxicity that may be involved in HD. The various striatal chemical markers display a highly heterogeneous distribution pattern in human. In addition to the classic striosomes/matrix compartmentalization, the striosomal compartment itself is composed of a core and a peripheral region, each subdivided by distinct subsets of striatal interneurons. A proper knowledge of all these features that appear unique to humans should greatly help our understanding of the organization of the human striatum in both health and disease states.

Corpus Striatum↗
PubMed2000

Characterization of the subventricular zone of the adult human brain: evidence for the involvement of Bcl-2.

The subventricular zone (SVZ) is an embryonic remnant that persists and remains mitotically active throughout adulthood. The rodent SVZ harbors neuronal precursors, principally in its anterior part, and generates neuroblasts that migrate tangentially into the olfactory bulb, thus forming the so-called rostral migratory stream. This study aimed at characterizing the SVZ in the human brain. Antibodies raised against the widely used SVZ molecular markers nestin, glial fibrillary acidic protein, beta-tubulin-III and polysialylated neural cell adhesion molecule, have allowed us to characterize in detail a zone similar to the rodent SVZ in humans. Virtually all portions of the lateral ventricle, as well as the ventral (hypothalamic) sector of the third ventricle, displayed immunoreactivity for most of the molecular markers. The midline region of the septum (septal recess) and the ventral portion of the SVZ displayed a particularly intense immunostaining for all SVZ markers. These two regions may represent zones of adult neurogenesis that are unique to primates. Furthermore, the anti-apoptotic protein Bcl-2 was found to be actively synthesized and co-expressed with all the other markers throughout the entire SVZ. This study reveals that a well-developed SVZ exists in the adult human brain and suggests that Bcl-2 might play an important role in the functional organization of such a system.

Adolescent↗
PubMed2000

The organization of the striatal output system: a single-cell juxtacellular labeling study in the rat.

The aim of the present study was to provide a detailed account of the axonal branching pattern of striatal projection neurons in the rat. Seventy-seven striatofugal neurons were singly labeled following juxtacellular injection of biotin dextran amine. Their axons were entirely reconstructed along the sagittal plane with the help of a light microscope equipped with a camera lucida. The major findings of this study can be summarized as follows, (1) the striatofugal system originates from medium-sized spiny neurons that project only to globus pallidus (GP, type I, 36.4%), to both GP and substantia nigra pars reticulata (SNr, type II, 26%), or to globus pallidus, entopeduncular nucleus (EP) and SNr (type III, 37.6%); (2) the striatofugal system displays a high degree of axonal collateralization; about two-thirds of its axons arborize into two or three striatal target structures; (3) virtually all striatofugal axons send collaterals to the GP and none project exclusively to the EP and or SNr; (4) the three types of striatal projection neurons share similar somatodendritic morphology and have no preferential distribution in the dorsal striatum. These data, together with those of previous investigations, indicate that the striatofugal system can no longer be considered to be a simple dual (direct indirect) projection system. Instead, it stands out as a complex and widely distributed neuronal network whose elements are endowed with a highly patterned set of axon collaterals, which allows them to control in an exquisitely precise manner the flow of information along the main axis of the basal ganglia.

Animals↗