Biomedical subjects

N Zecevic

Publications and source records attributed to N Zecevic.

29 records · Page 2Linked to original sources

PubMed1995

Immunocytochemical localization of growth-associated protein GAP-43 in early human development.

Fibers labelled with antibody to the growth associated protein (GAP-43) were observed as early as 4 gestational weeks (g.w.) in the nervous system of human embryos. At 6 g.w. these fibers could be traced throughout the brainstem and the diencephalon. None of the immunolabeled fibers entered the telencephalic wall at that point, but 2 weeks later at 8 g.w., GAP-43 positive fibers were observed below the newly formed cortical plate of the cerebral cortex. GAP-43 positive fiber bundles had the same distribution as those previously labeled with tyrosine hydroxylase antibodies at the same age. These results strongly suggest that this growth associated protein is localized in the early growing dopaminergic fibers.

Brain↗

PubMed1995

Development of the catecholamine neurons in human embryos and fetuses, with special emphasis on the innervation of the cerebral cortex.

The cathecholaminergic (CA) systems have been described as appearing early in the development of the mammalian central nervous system (CNS), but their exact distribution in humans has been studied only following gestational week (g.w.) 13. Furthermore, it is not known when CA fibers initially penetrate the developing cerebral cortex. In this study, the CA cells groups and fibers are described in the human central nervous system from 6 to 13 g.w. as revealed with immunocytochemical techniques, with antibodies raised against three synthetic enzymes of the catecholamine (CA) pathway: tyrosine hydroxylase (TH), dopamine-beta-hydroxylase (DBH), and phenylethanolamine-N-methyltransferase (PNMT). At 6 g.w., TH-like immunoreactive (TH-IR) cell groups were widespread through the caudorostral extension of the CNS corresponding to the different dopaminergic mesencephalic and hypothalamic groups. Noradrenergic groups also were labeled in the medulla oblongata and in the locus coeruleus as well as in other areas in the pons. Additional TH-IR cell groups might represent a transient developmental expression of TH similar to that observed in the rat. DBH immunoreactivity labeled primarily the noradrenergic pontic cell groups and, to a lesser extent, groups located in the medulla oblongata. Rare PNMT-IR neurons were detected in the medulla oblongata only at 13 g.w. The main CA bundles described in the adult were also observed in human embryos and fetuses. At 6 g.w., TH-IR pathways extended caudorostrally within the central tegmental tract and the dorsal tegmental bundle, the latter merging with the dopaminergic mesotelencephalic pathway giving rise to the medial forebrain bundle in the basal forebrain. At 7-8 g.w., TH-IR fibers extended to the basal ganglia and the telencephalic wall. The first TH-IR and, to a much lesser extent, DBH-IR fibers penetrated the frontal lateral cortical anlage through the intermediate zone and sparsely through the marginal zone but not through the thin cortical plate. A second stream entered the telencephalic anlage frontomedially, ventral to the septal area. At 11 g.w., numerous TH-IR fibers invaded the subplate layer, but they penetrated the cortical plate only at 13 g.w. At that time, TH-IR and DBH-IR fibers had reached the occipital cortex in a rostrocaudal gradient. The appearance of well-organized CA system already in embryonic stages in humans could be of great importance for normal shaping of the nervous system as well as for development of cortical circuitry.

Adrenergic Fibers↗

PubMed1992

Early appearance of tyrosine hydroxylase immunoreactivity in the retina of human embryos.

In the retina of 6 post-ovulatory week old human embryos, tyrosine hydroxylase (TH) immunoreactivity is expressed in retinoblasts in the peripheral retina, and ganglion-like cells with an axon in the optic nerve in the posterior retina. This is the first report on the expression of a catecholamine marker in a sub-population of migrating retinoblasts. Since in the adult retina the only TH+ cells are a sub-population of amacrine cells, the expression of this enzyme in some ganglion-like cells must represent either a transient developmental event, or indicate that these cells subsequently undergo transformation through axonal degeneration.

Abortion, Legal↗

PubMed1991

Early evidence of catecholaminergic cell groups in 5- and 6-week-old human embryos using tyrosine hydroxylase and dopamine-beta-hydroxylase immunocytochemistry.

Catecholaminergic systems were visualized in the CNS of human embryos from stage 15-16 (5 gestational week, g.w.) to 18 (6 g.w.) using tyrosine hydroxylase (TH) and dopamine-beta-hydroxylase (DBH) as immunocytochemical markers. At 5 g.w., several TH-like immunoreactive (TH-IR) cell groups were identified in the medulla oblongata, pons, mesencephalon and the anlage of the hypothalamic area. DBH immunoreactivity was restricted to the locus coeruleus and to rare neurons in the medulla oblongata. At 6 g.w., the density of TH-IR neurons was strikingly increased in these different areas--especially in the prospective substantia nigra and ventral tegmental area--and two main bundles of catecholaminergic axons extended from the medulla oblongata until the basal forebrain and from the mesencephalic tegmentum to the anlage of the striatum. These pathways were mainly TH-IR but DBH-IR was also observed in the former. No TH-IR fibers reached the telencephalon at 6 g.w.

Brain↗

PubMed1989

Changes in synaptic density in motor cortex of rhesus monkey during fetal and postnatal life.

The density and proportion of synaptic contacts in the primate motor cortex (Brodmann area 4) were determined in 21 rhesus monkeys ranging in age from embryonic day 41 (E41) to 20 years. Two to 4 vertical electron microscopic probes, each consisting of 150-250 overlapping micrographs traversing the thickness of the cortex, were prepared for each specimen. Synapses were categorized according to their morphology (symmetrical or asymmetrical), cellular location (on spines, shafts or soma), number, and ratio of laminar distribution. The density of synapses was expressed per unit area and volume of neuropil (excluding neuronal and glia cell bodies, myelin sheath, blood vessels and extracellular space). The first synapse in the area of the emerging motor cortex were observed at E53 in the marginal zone (prospective layer I) and in the transient subplate zone situated beneath the developing cortical plate. Around midgestation (E89) synapses were observed over the entire width of the cortical plate, and their density was about 5/100 microns 3 of neuropil. During the last two months of gestation synaptic density increased 8-fold across all layers to reach about 40/100 microns 3 at the time of birth (E165). Synaptic production continued postnatally and by the end of the second postnatal month attained a level of 60/100 microns 3 neuropil which is two times higher than in the adults. This level decreased at a slow rate until sexual maturity (3 years of age) and then more rapidly to the adult level which is characterized by relative stability of about 30/100 microns 3. The decline in synaptic density after the peak in infancy occurs predominantly at the expense of asymmetric synapses situated on dendritic spines; the population of symmetric synapses on dendritic shafts remains relatively constant. The development of synaptic connections in the motor cortex of non-human primates involves initial overproduction followed by selective elimination and structural alterations.

Aging↗

PubMed1986

Concurrent overproduction of synapses in diverse regions of the primate cerebral cortex.

Synapses develop concurrently and at identical rates in different layers of the visual, somatosensory, motor, and prefrontal areas of the primate cerebral cortex. This isochronic course of synaptogenesis in anatomically and functionally diverse regions indicates that the entire cerebral cortex develops as a whole and that the establishment of cell-to-cell communication in this structure may be orchestrated by a single genetic or humoral signal. This is in contrast to the traditional view of hierarchical development of the cortical regions and provides new insight into the maturation of cortical functions.

Animals↗

PubMed1986

Development of the human dentate nucleus.

The developing human dentate nucleus (DN) was studied in a series of specimens of various pre- and postnatal ages ranging from 8 gestational weeks (gw) to 10 years, in Golgi-impregnated and Nissl-stained material. The DN emerges from the cerebellar white matter at around 16 gestational weeks (gw) as a thick band of cells (600-700 micron in width) that gradually attenuates to a final width of 150-250 micron as it undergoes extensive infolding beginning around 24 gw. The highly convoluted configuration of the adult DN is recognizable by 35 gw. Around 16 gw, two basic classes of DN neurons can be identified. Differentiation of these neurons is especially intensive during the mid-gestational period (20-25 gw). At this time the size of cell bodies increases, dendrites branch profusely and acquire spines. A second, slower phase of maturation consisting of addition of secondary and tertiary branches, continues into the postnatal period. At all prenatal ages examined, dentate neurons are morphologically more mature than the Purkinje cells in the overlying cortex. DN neurons of premature infants did not show cytomorphological differences when compared with babies born at term.

Cerebellar Nuclei↗

PubMed1976

Differentiation of Purkinje cells and their relationship to other components of developing cerebellar cortex in man.

The differentiation of Purkinje cells and their relationship to other components of the developing cerebellar cortex were analyzed by the Golgi impregnation method and by electron microscopy in human specimens of various pre- and postnatal ages. The three stages of Purkinje cell maturation that have been previously recognized in other species are also evident in man: the first stage occupies primarily the fourth fetal month (12-16 weeks); the second stage lasts through the fifth, sixth and seventh feta months (16-28 weeks); the third stage extends throughout the remaining period of intrauterine life and the first postnatal year and continues at a slow rate thereafter. During the first stage, Purkinje cells are distributed in a layer, several rows deep. Their bipolar somas are relatively smooth and have only a few processes at the apical and basal cell poles. In the 3-month period of the second stage, Purkinje cells become gradually organized into a single row. Their somas become invested with additional randomly oriented dendritic processes and numerous somatic spines (pseudopodia). The first morphologically well-defined synapses appear on the Purkinje cell somatic spines and on their immature dendritic shafts at the beginning of the second stage and become more prominent during the period from 18 to 24 weeks. In the third stage, the dendritic arbor becomes flattened in the plane transverse to the folium and somatic spines disappear. Spines appear on the secondary and tertiary dendrites between the twenty-fourth and twenty-eighth fetal weeks and continue to increase in number during the entire third stage as new dendritic branches develop. These observations indicate that cellular maturation and synaptogenesis in the primate cerebellum differ from these events in non-primate species, with respect to time of birth, in the relative duration of each phase and in the total time necessary for neuronal differentiation. The protracted time of differentiation and the slow growth of Purkinje cell dendrites in man may be due to the numerically complex relationships existing between granule and Purkinje cells. It is probably not simply a reflection of the larger size of human Purkinje cells and their dendrites.

Animals↗

PubMedDate not supplied

Synaptogenesis in monkey somatosensory cortex.

The time course and rate of synaptogenesis were studied in the somatosensory cortex (Brodmann's areas 1 and 3b) of 27 rhesus monkeys ranging in age from embryonic day 41 to 20 years. Two to four vertical probes, each consisting of a series of overlapping electron micrographs and extending from the pial surface to the interface of the cortex with the white matter, were made from sections cut across the postcentral gyrus in the region of the upper limb representation. We found that the density of synapses per unit volume of cortex as well as per unit volume of neuropil increases steadily throughout the late fetal ages and early infancy. A density of 70/100 microns 3 of neuropil was reached by the second postnatal month; thereafter, between 1 and 3 years a slightly lower density of 50-60/100 microns 3 was maintained. At around puberty, the decrease in concentration of synapses appears to be accelerated. Thus, the average synaptic density of a group of 10 adult animals composed of monkeys over 4 years of age was 30-40 synapses per 100 microns 3 of neuropil. This value is significantly lower than that of the group of 11 infant and juvenile animals below 4 years of age. Since synaptic density per unit volume of neuropil is not affected by changes in other parameters of cortical growth, these numbers reflect an actual overproduction of synapses in infancy followed by their elimination during adolescence. The decline in the number of synapses is due primarily to elimination of asymmetrical junctions located on dendritic spines while symmetrical synapses on dendritic shafts and cell bodies remained relatively constant during postnatal life. The course of synapse formation recorded in the present study coincides with the course of overproduction and elimination of neurotransmitter receptors (Lidow et al., 1991) and the developmental schedule of synaptogenesis in other neocortical areas (Rakic et al., 1986). The timing of synaptogenesis and synaptic elimination in the postcentral gyrus may account for the maturation and plasticity of various aspects of somatosensory function during post-natal life.

Aging↗

PubMedDate not supplied

Synaptogenesis in layer I of the human cerebral cortex in the first half of gestation.

The formation of synapses is among the most important steps in neuronal differentiation and the establishment of neuronal circuits. To establish baseline data about the time of onset, density and the course of synaptic formation in different regions of the human cerebral cortex before birth, synaptogenesis in layer I was examined by electron microscopy in fetuses ranging in age from 6 to 24 gestational weeks. Synapses were first observed in the primordial plexiform layer (marginal zone) in both the lateral and medial cerebral walls between the 6th and 7th gestational week, before the formation of the cortical plate. The density of synapses increased rapidly after the formation of the cortical plate, increasing by 37% between 12 and 14 weeks. Synaptogenesis proceeded at the same rate in the lateral and occipital cortex during this period. Further, with one exception, the insular region, synaptic density was comparable in prospective areas of prefrontal, motor, visual, temporal and cingulate cortex in a group of fetuses at midgestation (20 weeks). The results are consistent with a synchronous course of synaptogenesis of the neocortex.

Analysis of Variance↗

PubMedDate not supplied

GRO-alpha and CXCR2 in the human fetal brain and multiple sclerosis lesions.

Chemokines, small proinflammatory cytokines, are involved in migration of inflammatory cells, but also have a role in normal central nervous system development. One chemokine, growth-related oncogene-alpha (GRO-alpha) and its receptor CXCR2, are involved in proliferation and migration of oligodendrocyte progenitors in rats. Here we studied the regional and cell type-specific expression of GRO-alpha and CXCR2 in the human telencephalon at midgestation, the time that oligodendrocytes are being generated in the human brain. Our results showed that both GRO-alpha and CXCR2 are predominately expressed by oligodendrocyte progenitors and activated microglial cells in the highly proliferative subventricular zone. This cellular and regional localization suggests that GRO-alpha/CXCR2 may play a role in human oligodendrocyte proliferation and subsequent migration. We also studied the expression of GRO-alpha and CXCR2 in brain sections of multiple sclerosis (MS) patients. Consistent with their role in the inflammatory process of MS, both GRO-alpha and CXCR2 were expressed in activated microglia localized on the border of MS lesions. However, neither GRO-alpha nor CXCR2 were present in early oligodendrocyte progenitors, a finding that may partially explain why remyelination is not more efficient in MS.

Astrocytes↗