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PubMed1988

Specification of cerebral cortical areas.

How the immense population of neurons that constitute the human cerebral neocortex is generated from progenitors lining the cerebral ventricle and then distributed to appropriate layers of distinctive cytoarchitectonic areas can be explained by the radial unit hypothesis. According to this hypothesis, the ependymal layer of the embryonic cerebral ventricle consists of proliferative units that provide a proto-map of prospective cytoarchitectonic areas. The output of the proliferative units is translated via glial guides to the expanding cortex in the form of ontogenetic columns, whose final number for each area can be modified through interaction with afferent input. Data obtained through various advanced neurobiological techniques, including electron microscopy, immunocytochemistry, [3H]thymidine and receptor autoradiography, retrovirus gene transfer, neural transplants, and surgical or genetic manipulation of cortical development, furnish new details about the kinetics of cell proliferation, their lineage relationships, and phenotypic expression that favor this hypothesis. The radial unit model provides a framework for understanding cerebral evolution, epigenetic regulation of the parcellation of cytoarchitectonic areas, and insight into the pathogenesis of certain cortical disorders in humans.

Afferent Pathways↗
PubMed1999

Effects of the thalamus on the development of cerebral cortical efferents in vitro.

The cerebral cortex is a multilayered tissue, with each layer differing in its cellular composition and connections. Axons from deep layer neurons project subcortically, many to the thalamus, whereas superficial layer neurons target other cortical areas. The mechanisms that regulate the development of this pattern of connections are not fully understood. Our experiments examined the potential of the thalamus to attract and/or select neurites from appropriate cortical layers. First, we cocultured murine cortical slices in close proximity to thalamic explants in collagen gels. The amount of neurite outgrowth from deep layer cells was enhanced by, but not attracted to, the thalamic explants. Second, we cocultured cortical slices in contact with thalamic or cortical explants to test for laminar specificity of connections. Specificity was apparent after culture for about a week, in that deep cortical layers contained the highest proportions of corticothalamic cells and superficial cortical layers contained the highest proportions of corticocortical cells. After shorter culture of only a few days, however, specificity was not apparent and there were larger numbers of corticothalamic projections from the superficial layers than after a week. To study how the early nonspecific pattern of corticothalamic connections was transformed into the more specific pattern, we labeled corticothalamic cells early, after 2 days, but let the cultures survive for 8 days. On day 8, the nonspecific pattern of early-labeled cells was still seen. We conclude that although the thalamus does not block the initial entry of inappropriate axons from the superficial layers, many of these axons are subsequently lost. This suggests that contact-mediated interactions between cortical axons and the thalamus allow cortical efferents from appropriate layers to be distinguished from those arising in inappropriate layers. This may contribute to the development of layer-specific cortical connections in vivo.

Animals↗
PubMed2005

Mph2 expression in germinal zones of the mouse brain.

The telencephalon develops from a seemingly homogeneous population of precursor cells that generates neurons with divergent properties and cell fates. An important question concerns the genetic control of cell states belonging to different generations. Mph2 was identified by serial analysis of gene expression as a differentially expressed gene during cortical development. Belonging to the Polycomb group, Mph2 may be involved in transcriptional repression of cell states from one generation to the next. Here, we use in situ hybridization to determine the spatial localization of Mph2 expression in the developing nervous system. Mph2 expression evident in proliferating precursor cell populations in the developing mouse brain such as the ventricular zones of the cortex and ganglionic eminences as well as in mature structures such as the granule cell layer of the adult dentate gyrus and cerebellum indicates a role for Mph2 in both the developing and adult brain.

Animals↗
PubMed1991

Expression of acidic fibroblast growth factor mRNA in the developing and adult rat brain.

We have localized acidic fibroblast growth factor (aFGF) mRNA in the developing and adult rat brain using in situ hybridization histochemistry. Prenatally, hybridization to aFGF mRNA was observed throughout the brain, with the strongest signal associated with cells of the developing cortical plate. Postnatally, labeling was localized to specific neuronal populations. In the hippocampus, labeling of the pyramidal cell layer and dentate granule cells was observed and became progressively more intense with maturation. Labeling was also observed in both the external and internal granule cell layers of the developing cerebellum. Pyramidal cells of the neocortex as well as neurons of the substantia nigra and locus ceruleus also express aFGF. This pattern persists into adulthood, although the intensity of the labeling is significantly reduced in the adult brain. These patterns of hybridization correlate with specific developmental events and suggest that aFGF plays a significant role in both central nervous system development and neuronal viability in the adult brain.

Animals↗
PubMed1989

Magnetic resonance imaging of disturbances in neuronal migration: illustration of an embryologic process.

Twenty-three cases of suspected congenital anomalies involving disorders of cortical proliferation, migration or cortication were retrospectively collected over an 18 month period. Pathologic confirmation was present in five cases. The theoretical sequential stages of cortical development are discussed as keys to the interpretation of MR images of anomalies resulting from arrest of the developmental process. MRI is the imaging modality of choice for suspected defects of cortex formation since it distinguishes gray from white matter, delineates the corticomedullary junction, records details of cortical surfaces, detects abnormal white matter, identifies heterotopias and records unrelated congenital abnormalities. Histopathologic confirmation of two cases of isolated heterotopia and three cases of polymicrogyria were available. Comparative images of MR, CT and pathologic specimens are presented.

Brain↗
PubMed1985

Studies of the earliest generated cells of the cat's visual cortex: cogeneration of subplate and marginal zones.

The earliest generated cells of the cat's telencephalon that may play a role in the formation of the primary visual cortex are the subject of this study. Using [3H]thymidine autoradiography, we have found that these cells are generated between embryonic day 24 (E24) and E30 (gestation is 65 days) and that they are present in very low numbers in the white matter of the adult brain. These cells are rarely labeled by injections made after E30, when the cells destined for the cortical layers are generated. Examination of the labeling pattern in the fetal brain 10 days or more after administration of [3H]thymidine between E24 and E30 revealed a bistratified distribution of these early generated cells. Labeled cells were found in large numbers in two embryonic zones flanking the developing cortical plate: above in the marginal zone and below in the subplate. (Some if not all of the marginal zone cells constitute the population of Cajal-Retzius cells of the cat's telencephalon.). These experiments indicate that cells of the subplate and marginal zones are cogenerated in time during the days just preceding the genesis of the cortical plate. We also examined the distribution of the early generated cells shortly after their genesis--on E30, a time when cells of the cortical plate are just being generated at the ventricular zone. In this case, the labeling pattern at the occipital pole was not bistratified. Rather, labeled cells were situated within a single zone extending from the pial surface inward to the border of the ventricular zone. This finding indicates that the cells of the subplate and marginal zones are generated as a contiguous population that is subsequently split apart by the insertion of cells forming the cortical plate. A comparison between the number of early generated cells found in fetal and newborn brains with that found in adult brains suggests that these cells are generated initially in substantial numbers but then largely disappear during early postnatal life, since injections of [3H]thymidine between E24 and E30 yielded large numbers of labeled cells in the white matter and layer 1 at birth, but very few at 2 months postnatal. This significant loss contrasted with the results from injections made just a few days later (E33) that resulted in large numbers of labeled cells in cortical layer 6 not only at birth but also in adulthood.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗
PubMed1989

Activators of protein kinase C trigger cortical granule exocytosis, cortical contraction, and cleavage furrow formation in Xenopus laevis oocytes and eggs.

Prophase I oocytes, free of follicle cells, and metaphase II eggs of the amphibian Xenopus laevis were subjected to transient treatments with the protein kinase C activators, phorbol 12-myristate 13-acetate (PMA), phorbol 12,13-didecanoate, and 1-olyeoyl-2-acetyl-sn-glycerol. In both oocytes and eggs, these treatments triggered early events of amphibian development: cortical granule exocytosis, cortical contraction, and cleavage furrow formation. Surprisingly, activation of oocytes occurred in the absence of meiotic resumption, resulting in cells with an oocytelike nucleus and interior cytoplasm, but with a zygotelike cortex. PMA-induced activation of oocytes and eggs did not require external calcium, a prerequisite for normal activation of eggs. PMA-induced activation of eggs was inhibited by retinoic acid, a known inhibitor of protein kinase C. In addition, pretreatment of eggs with retinoic acid prevented activation by mechanical stimulation and inhibited activation by calcium ionophore A23187. The results suggest that protein kinase C activation is an integral component of the Xenopus fertilization pathway.

Animals↗
PubMed2004

Postnatal development of the cerebellum and the CNS adrenergic system is independent of norepinephrine and epinephrine.

A fundamental question in the formation of the nervous system is the extent to which a neurotransmitter contributes to the development of the neurons that synthesize and release it. A complementary question is whether neurotransmitter signaling contributes to the development of postsynaptic targets. Prior studies have suggested that adrenergic signaling may promote adrenergic neuronal proliferation or survival and may be critical for the postnatal development of the cerebellum. To test these possibilities genetically, we studied mice that are unable to synthesize norepinephrine and epinephrine (NE/E), the endogenous adrenergic receptor ligands, due to a disruption the gene for dopamine beta-hydroxylase. These mice develop postnatally in the absence of NE/E. Here we report that the adrenergic neurons of these mutant mice are present in normal numbers and locations and exhibit typical innervation patterns throughout the central nervous system (CNS), as assessed by immunostaining for tyrosine hydroxylase and the NE transporter. Furthermore, cerebellar cortical development (size, foliation, layering, cell number, and position), which proceeds to a large degree postnatally, is unaltered in the mutants. These results indicate that the fate and innervation pattern of the adrenergic neurons, as well as the development of the cerebellum, do not depend on postnatal signaling by NE/E. The results also suggest that when restoration of adrenergic signaling is performed in this mutant mouse model (by administering a synthetic precursor of NE), reversal of phenotypes is due to the synthesis and release of NE/E from adrenergic terminals that are distributed normally within the CNS.

Age Factors↗
PubMed2002

The surface of the developing cerebral cortex: still special cells one century later.

The marginal zone of the developing cerebral cortex is formed by different types of neurons, some of which were described more than one century ago. It is the case of Cajal-Retzius cells, which are known to synthesize and secrete Reelin, an extracellular matrix glycoprotein critically involved in the radial migration and early cortical cytoarchitectonic organization. These cells do not emit projection axons, a characteristic that bespeaks against these cells being considered as pioneer neurons. The true pioneer neurons of the marginal zone are part of a distinct cell entity: these are cells that emit the earliest descending axonal projection from the cerebral cortex into the subpallium, even before than subplate neurons, the other population of pioneer neurons in the cortical anlage. Finally, the marginal zone is a territory where cohorts of undifferentiated cortical interneurons migrate into the upper layers of the cerebral cortex. Marginal zone neurons, including Cajal-Retzius cells, tend to distribute non-uniformly over the cortical surface. Such a mosaic structural configuration points towards more complexities regarding their possible functions during cortical development.

Animals↗
PubMed2003

Segregation and coactivation of developing neocortical layer 1 neurons.

Layer 1 in the developing cerebral cortex is populated by two basic neuronal cell types, Cajal-Retzius (CR) cells and non-CR cells. We generated transgenic mice in which green fluorescent protein (GFP) was driven by the promoter of metabotropic glutamate receptor subtype 2 and expressed specifically in CR cells during cortical development. On the basis of the precise identification of CR cells with GFP fluorescence, we pursued developmental changes and synaptic mechanisms of both CR and non-CR cells during the postnatal period. Immunostaining in combination with GFP fluorescence imaging showed that GFP and reelin, a protein involved in corticogenesis, completely overlap in CR cells at postnatal day 0. At the subsequent postnatal stage, reelin-positive neurons are segregated and categorized into GFP-positive/GABA-negative CR cells and GFP-negative/GABA-positive non-CR cells. Individual and simultaneous whole-cell recordings of CR and non-CR cells in developing cerebral slices revealed that spontaneous and electrically evoked postsynaptic currents (sPSCs and ePSCs) measured in CR and non-CR cells are differentially mediated by GABA(A) receptors versus GABA(A), AMPA, and NMDA receptors, respectively. Furthermore, CR and non-CR cells show synchronized repetitive barrages of sPSCs that reflect a network-driven activity in the developing cerebral cortex. These findings imply that the layer 1 neurons dynamically change and play a distinct and integral role in the postnatal developing neocortex.

Animals↗
PubMed2004

Involvement of the phosphatidylinositol 3-kinase/rac1 and cdc42 pathways in radial migration of cortical neurons.

During cortical development, newly generated neurons migrate radially toward their final positions. Although several candidate genes essential for this radial migration have been reported, the signaling pathways regulating it are largely unclear. Here we studied the role of phosphatidylinositol (PI) 3-kinase and its downstream signaling molecules in the radial migration of cortical neurons in vivo and in vitro. The expression of constitutively active and dominant-negative PI 3-kinases markedly inhibited radial migration. In the neocortical slice culture, a PI 3-kinase inhibitor suppressed the formation of GTP-bound Rac1 and Cdc42 and radial migration. Constitutively active and dominant-negative forms of Rac1 and Cdc42 but not Akt also significantly inhibited radial migration. In migrating neurons, wild-type Rac1 and Cdc42 showed different localizations; Rac1 localized to the plasma membrane and Cdc42 to the perinuclear region on the side of the leading processes. These results suggest that both the PI 3-kinase/Rac1 and Cdc42 pathways are involved in the radial migration of cortical neurons and that they have different roles.

Animals↗
PubMed2003

Selective vulnerability of subplate neurons after early neonatal hypoxia-ischemia.

Neonatal hypoxia-ischemia in the preterm human leads to selective injury to the subcortical developing white matter, which results in periventricular leukomalacia (PVL), a condition associated with abnormal neurodevelopment. Maturation-dependent vulnerability of late oligodendrocyte progenitors is thought to account for the cellular basis of this condition. A high frequency of cognitive and sensory deficits with decreasing gestational age suggests pervasive abnormalities of cortical development. In a neonatal rat model of hypoxic-ischemic injury that produces the characteristic pattern of subcortical injury associated with human PVL, selective subplate neuron death is seen. The premature subplate neuron death occurs after thalamic axons have reached their targets in cortex. Thus, as expected, thalamocortical connections form normally, including patterned connections to somatosensory cortex. However, deficits in motor function still occur, as in babies with PVL. Subplate neuron cell death in PVL provides another mechanism for abnormal neurodevelopment after neonatal hypoxia-ischemia.

Animals↗
PubMedDate not supplied

Prenatal and postnatal contents of amino acid neurotransmitters in mouse parietal cortex.

This study documents the variation in the amino acid neurotransmitter contents during mouse parietal cortex development, from embryonic day 13 (E13) until young adulthood, between postnatal day 21 (P21) and P30. Taurine, an inhibitory neurotransmitter and neuromodulator, is the most abundant neurotransmitter in the developing neocortex, whereas, at the adult stage, glutamate is the more prominent neurotransmitter playing an excitatory role, and GABA is the major inhibitory neurotransmitter. During the proliferative stage of neurogenesis in the mouse cerebral cortex, between E13 and E17, relatively high levels of glutamate, aspartate, taurine and glycine were detected, consistent with a possible trophic influence of these neurotransmitters during cortical development prior to synaptogenesis. Between E17 and E19, a significant decline in the contents of these neurotransmitters was observed, consistent with earlier reports of cell death in the ventricular and subventricular zones during this stage of development. During the perinatal period, a progressive increment in glutamate level was seen between E21 and P5, and then the values remained constant until the second postnatal week. Glutamate also decreased by about 25% between P11 and P15, on the other hand, aspartate diminished by about 20% between P7 and P9. These results were consistent with previous reports of histogenetic cell death during the first 2 postnatal weeks in mouse neocortex. GABA increased from the embryonic period until young adulthood, in contrast, the glycine content decreased; thus, in the adult parietal cortex, the GABA content was about 2.6-fold higher than that of glycine. During the first postnatal week, the concentrations of glutamate and GABA showed significant increments between P0 and P5, while those of aspartate and glycine remained constant. During this period, amino acids are predominantly excitatory and the cerebral cortex is vulnerable to epileptiform activity; the significant increment in taurine content between P0 and P3 suggests a neuroprotective action of taurine against excitotoxicity. At P15, coinciding with the period of maximum cortical synaptogenesis, significant increments in GABA and glycine contents were observed which could be related to the maturation of inhibitory synaptic transmission. At the young adult stage, there was a rise in the levels of both excitatory neurotransmitters, glutamate and aspartate, and a significant reduction in the contents of all three inhibitory neurotransmitters, GABA, glycine and taurine.

Animals↗
PubMed1994

The intrinsic geometry of the cerebral cortex.

The mammalian cerebral cortex is a profoundly convoluted six-layered surface. The expansion of the cortex during evolution appears to be due to an increase in the number of functional units as opposed to an increase in the complexity of the units. Geometric similarity predicts that cortical area should increase in proportion to the 2/3 power of cortical volume. Allometric analysis has shown that in fact cortical area increases as a nearly linear function of cortical volume. This can be understood by appreciating that smaller brains tend to be smooth (lissencephalic) and larger brains fissured (gyrencephalic). This process of fissuration has reached its modern terrestrial limit in the human brain where the majority of the cortical surface is hidden within folds. The thickness of the cortex (2-3 mm) is small compared to its area (2000-2500 cm2) so the application of the techniques of differential geometry (the mathematics of idealized surfaces) is justified. Geometric properties of surfaces fall into two categories: intrinsic properties (which are invariant under folding of the surface, e.g. distances measured on the surface) and extrinsic properties (pure folding). The extrinsic geometry of the cortex determines the anatomical appearance of the cortex and the shape of the white matter. The intrinsic curvature of the cortex affects the relative position of functional areas and the spread of activity within the surface itself. A cortical surface has been reconstructed from cross-sections. Analysis of this surface has shown that the cortex has significant intrinsic curvature and hence it is wrong to regard it as merely a crumpled bag. The particular geometry observed is such that the surface is peculiarly "close together". Theoretical considerations and simulations suggest that the intrinsic geometry may have a significant effect on: the necessity of non-uniform growth in models of cortical development; the location of integrative areas; and the synchronization of neuronal firing. It is suggested that intrinsic descriptions of the cortex may prove more natural than extrinsic ones.

Anthropometry↗
PubMed2000

delta-catenin is a nervous system-specific adherens junction protein which undergoes dynamic relocalization during development.

delta-catenin is a member of the Armadillo repeat family and component of the adherens junction discovered in a two-hybrid assay as a bona fide interactor with presenilin-1 (Zhou et al., [1997], NeuroReport 8:2085-2090), a protein which carries mutations that cause familial Alzheimer's disease. The expression pattern of delta-catenin was mapped between embryonic day 10 (E10) and adulthood by Northern blots, in situ hybridization and immunohistochemistry in the mouse. In development, delta-catenin is dynamically regulated with respect to its site of expression. It is first expressed within proliferating neuronal progenitor cells of the neuroepithelium, becomes down-regulated during neuronal migration, and is later reexpressed in the dendritic compartment of postmitotic neurons. In the mouse, delta-catenin mRNA is expressed by E10, increases and peaks at postnatal day (P)7, with lower levels in adulthood. In the developing neocortex, delta-catenin mRNA is strongly expressed in the proliferative ventricular zone and the developing cortical plate, yet is conspicuously less prominent in the intermediate zone, which contains migrating cortical neurons, delta-catenin protein forms a honeycomb pattern in the neuroepithelium by labeling the cell periphery in a typical adherens junction pattern. By E18, delta-catenin expression shifts primarily to nascent apical dendrites, a pattern that continues through adulthood. The dynamic relocalization of delta-catenin expression during development, taken together with previously published data which described a role for delta-catenin in cell motility (Lu et al., [1999] J. Cell. Biol. 144:519-532), suggests the hypothesis that delta-catenin regulation is closely linked to neuronal migration and may play a role in the establishment of mature dendritic relationships in the neuropil.

Animals↗
PubMed2002

Mechanisms regulating lineage diversity during mammalian cerebral cortical neurogenesis and gliogenesis.

During mammalian cerebral cortical development, neural stem cells (NSCs) present within periventricular generative zones give rise to successive waves of neurons and radial glia, followed by oligodendrocytes and astrocytes. The molecular and cellular mechanisms that orchestrate these precisely timed and progressive maturational events are still largely undefined. These developmental processes are likely to involve the dynamic interplay of environmental signals, cell-cell interactions and transcriptional regulatory events. The bone morphogenetic proteins (BMPs), an expanding subclass of the transforming growth factor beta cytokine superfamily, may represent an important set of environmental cues for these progressive maturational events because of the broad profiles of developmental expression of the requisite BMP ligands, receptor subunits and intracellular transduction elements, and because of their versatile roles in promoting a spectrum of cellular processes intimately involved in progressive neural fate decisions. The BMPs also interact with complementary regional environmental signals such as the basic fibroblast growth factor (bFGF) and sonic hedgehog (Shh) that promote earlier stages of NSC expansion, self-renewal, lineage restriction and incipient lineage commitment. The ability of these cytokines and trophic signals to act within specific neurodevelopmental contexts may, in turn, depend on the composite actions of cell-cell contact-associated signals, such as Notch-Hes-mediated lateral inhibitory pathways, and additional transcriptional modulatory events, such as those mediated by members of the inhibitor of differentiation (ID) gene family that encode a novel set of negative basic helix-loop-helix (bHLH) transcription factors. In this chapter, we will examine the distinct roles of these different classes of developmental cues in defining the biological properties of an integrated cerebral cortical developmental signaling network. Ongoing studies in this exciting area of mammalian central nervous system (CNS) development will help to identify important molecular and cellular targets for evolving pharmacological, gene and stem cell therapeutic interventions to combat the pathological sequelae of a spectrum of acquired and genetic disorders of the central nervous system.

Animals↗
PubMed2000

Functional magnetic resonance imaging of the normal and abnormal visual system in early life.

Functional magnetic resonance imaging (fMRI) in young children may provide information about the development of the visual cortex, and may have predictive value for later visual performance. The purpose of this study was to evaluate the usefulness of fMRI for examining cerebral processing of vision in very young infants and in infants with brain damage. We examined 15 preterm infants, 12 children suspected of having a cerebral visual impairment and 10 children with a normal visual system, all of whom were either spontaneously asleep or sedated with chloral hydrate. Cortical response to stroboscopic light stimulation could be demonstrated in all technically acceptable data sets from children with a post-menstrual age (PMA) of > 41 weeks, but not in younger infants. Children < 60 weeks PMA showed either a blood oxygenation level-dependent (BOLD) signal increase or decrease, while all older children showed a signal decrease. The activated cortical volumes showed a linear relation to age for healthy children younger than 90 weeks PMA, but were small in children with visual impairment. In two children with unilateral damage to the optic radiations, activation was strongly asymmetrical with greatest activation on the healthy side. In future prospective studies, results from the period from birth to six months of age should be interpreted with caution, as inter-individual variation of cortical development may be confused with functional deficit.

Blindness, Cortical↗
PubMed2000

[Cortical dysgenesis: current classification, MRI diagnosis, and clinical review].

Cortical dysgenesis comprises a heterogenous group of genetic or acquired disturbances of cortical development which, due to progress in modern neuroimaging techniques, are increasingly recognized in association with a variety of clinical disorders. The spectrum of clinical manifestations, depending on type and extent of the alterations, includes severe mental retardation and epilepsy as well as neuropsychological deficits and psychiatric disorders. Up to now, the nomenclature of cortical malformations has been difficult and ambiguous. Recently, the understanding and terminology of these disorders has been facilitated by the proposal of a new classification scheme based on pathophysiological as well as pathogenetic mechanisms. This proposal has been elaborated by a group of experts and is not yet well-known in the German literature. Magnetic resonance imaging (MRI) allows diagnosis and classification in many cases of cortical dysgenesis during lifetime, thereby helping to identify prognostic and therapeutic options. Early diagnosis of cortical malformations is of particular importance in patients with drug-resistant epilepsy, as they can either be cured or benefit from epilepsy surgery. This review gives examples of the most relevant cortical malformations using the new classification scheme and summarizes their clinical as well as MRI characteristics. Besides routine MRI applications, some experimental techniques are discussed which may help to identify even subtle alterations.

Brain Diseases↗