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PubMed2005

Regulation of cortical dendrite development by Rap1 signaling.

Rap1 is a small GTP-binding protein that has been implicated in intracellular signaling and cytoskeletal control. Here, we show that Rap1 is expressed in rat cortical neurons and plays a critical role in dendritic development. Inhibition of Rap1 signaling either by expressing dominant negative mutant of Rap1 or Rap1GAP in cortical neurons reduced dendritic complexity. In contrast, expression of a constitutively active mutant of Rap1 (Rap1V12) induced dendritic growth and branching. Membrane depolarization, which induces dendritic growth via calcium influx, led to a rapid activation of Rap1 via cAMP and cGMP signaling. A CREB-dependent mechanism is involved in depolarization-induced dendritic growth in cortical neurons. Rap1 function contributed to depolarization induced CREB activation, and inhibition of CREB suppressed dendritic growth induced by Rap1V12. These observations identify Rap1 as a key mediator of calcium regulation of CREB-dependent transcription and dendritic development.

Animals↗
PubMed1994

Competence to undergo normal, fertilization-induced cortical activation develops after metaphase I of meiosis in mouse oocytes.

The purpose of this study was to determine at what stage of meiotic maturation mouse oocytes develop the ability to undergo sperm-induced activation, assayed by cortical granule (CG) release. Germinal vesicle breakdown (GVBD), prometaphase I (proMI), metaphase I (MI), and metaphase II (MII, the normal stage at fertilization) stages were evaluated by quantitative image analysis. At 2 hr, fertilized MII eggs underwent a mean CG loss of 69%; loss was global--in the entire cortex occupied by CGs. In contrast, fertilized GVBD and proMI oocytes had no significant CG loss in the cortex after 2 hr. After 4 hr, 63, 67, and 88% of fertilized GVBD, proMI, and MI oocytes, respectively, had localized CG release only in the vicinity of the fertilizing sperm. At 4 hr, GVBD oocytes had small sperm-associated, CG-depleted domains, approximately 100 microns 2 (< 1% of the oocyte cortex), whereas those for proMI oocytes were approximately 2500 microns 2. The CG density was reduced by 90% in these domains, whereas the remaining cortex showed no evidence of CG loss. Both the extent and time course of CG loss were altered in oocytes fertilized before MII and were not significantly affected with 25 microM thimerosal, which sensitizes egg calcium stores. Unlike the ability to undergo CG release, the ability to initiate sperm chromatin decondensation was not stage specific and the extent of decondensation was cell cycle related. Competence to undergo CG loss develops in two phases: the ability to undergo localized CG release increases between the GV and MI stages, whereas the mechanism of propagating a normal wave of global CG loss from the site of sperm entry develops between MI and MII.

Animals↗
PubMed1997

Incidence and progression of cortical and posterior subcapsular opacities: the Longitudinal Study of Cataract. The LSC Group.

OBJECTIVE: The purpose of the study is to estimate incidence and progression rates of cortical and posterior subcapsular (PSC) opacities in the Longitudinal Study of Cataract (LSC). DESIGN: An epidemiologic study of the natural history of lens opacities in a clinic-based population. PARTICIPANTS: The LSC was based on 764 participants in an earlier case-control study of lens opacities. MAIN OUTCOME MEASURES: Baseline data, collected until 1988, included color slit and retroillumination photographs. The same data were collected at follow-up visits from 1989 to 1993. The Lens Opacities Classification System III (LOCS III) was used to assess lens changes between baseline and follow-up photographs. The product-limit method was used to estimate the incidence and progression rates. RESULTS: After 5 years of follow-up, the incidence rates for developing cortical and PSC opacities were 7.7% and 4.3%, respectively. The progression rate of pre-existing cortical opacities was 16.2% after 5 years, and was twice as high as the incidence rate. The progression of pre-existing PSC opacities was much higher, and reached 55.1% after 5 years of follow-up. The incidence of newly developed cortical or PSC opacities increased with age. The incidence of PSC opacities also increased when coexisting opacities were present at baseline. CONCLUSIONS: After 5 years, 1 in every 13 patients developed new cortical opacities, and 1 in 24 developed new PSC opacities. The 5-year progression rates for cortical and PSC opacities were much higher than the incidence rates. These results can be used to estimate the rate of cortical and PSC changes in similar populations.

Aged↗
PubMed1999

Cerebral cortical specification by early potential restriction of progenitor cells and later phenotype control of postmitotic neurons.

Neurons expressing latexin, a carboxypeptidase A inhibitor, are restricted to lateral areas in the cerebral cortex of adult and early postnatal rats. To address the precise timing of cortical regional specification at the cellular level, we monitored latexin expression in developing cortical cells under specific conditions in vitro. Individual cortical cells were labeled with 5-bromo-2'-deoxyuridine in vivo, dissociated and exposed to a defined new environment in a monolayer or a reaggregated-cell culture system. While a substantial fraction of early progenitor cells derived from the lateral cerebral wall became latexin-expressing neurons in both systems, far fewer progenitors from dorsal cortex did so under the same environmental conditions, indicating early establishment of cortical regional specification at the progenitor cell level. Furthermore, it was shown that the probability for postmitotic cells within lateral cortex to become latexin-expressing neurons was influenced by temporally regulated regional environmental signals. These findings suggest that developing cortical cells are progressively specified for a regional molecular phenotype during both their proliferative and postmitotic periods.

Animals↗
PubMed1991

The role of apoptosis in the development of renal cortical tubular atrophy associated with healed experimental renal papillary necrosis.

An animal model of chronic analgesic nephropathy, in which renal papillary necrosis was induced by the administration of a single injection of bromoethylamine 2-hydrobromide in male Sprague-Dawley rats, was used to investigate the pathogenesis of the atrophy of tubules that leads to cortical atrophy or 'scarring' in analgesic nephropathy. One of the major objectives was documentation of the participation of apoptosis, a distinctive mode of cell death, in the process of cortical tubular atrophy. Control and treated groups of animals were studied at 2 wks, and at subsequent monthly intervals up to 4 mths. At each time, light microscopy and ultrastructure were used to relate changes in cellular pathology to alterations in renal mass. Apoptosis was quantitated in paraffin sections, and autoradiographic identification of cells showing tritiated thymidine uptake was used as an indication of cell proliferation. In animals with total renal papillary necrosis (RPN), focal or diffuse cortical atrophy developed, the extent of which appeared to be proportional to the extent of the RPN. Renal mass was reduced only in those kidneys that developed extensive, diffuse lesions. Compensatory renal growth occurred in the areas of healthy tissue adjacent to the foci of atrophy, with both cellular hyperplasia and hypertrophy playing roles in its development. One of the prominent cellular events was the appearance of apoptotic cells and bodies, with invading intraepithelial macrophages involved in their phagocytosis and degradation. We propose that this form of cell death plays an important role in the pathogenesis of cortical atrophy. Current descriptions of the cortical lesions that occur in analgesic nephropathy refer to the changes as 'scars'. Although the focal lesions have a macroscopic appearance that resembles scars, the results of the present study indicate that usage of this terminology may be misleading, since scarring is often described after severe tissue injury or necrosis, which was not identified in the present study.

Animals↗
PubMed2003

[Congenital malformations of the cerebral brain. 1: Malformations of the cerebral cortex].

Disorders of supratentorial cortical development are usually divided into disorders of neuronal proliferation, neuronal migration and cortical organization. Based upon molecular biologic discoveries, a modified classification has recently been proposed. The category of malformations of abnormal neuronal and glial proliferation and apoptosis now includes microlissencephalies, megalencephalies, hemimegalencephalies and cortical dysplasias with balloon cells. Malformations due to abnormal neuronal migration now subsume the lissencephaly spectrum including the subcortical band heterotopias, the cobblestone complex and the group of heterotopias. Malformations due to abnormal cortical organization include the spectrum of polymicrogyria and schizencephaly as well as cortical dysplasias without balloon cells. High-resolution magnetic resonance imaging (MRI) has led to an increasing awareness of these malformations. This article aims to illustrate the classification, MRI presentation and relevant clinical features of the most commonly encountered disorders of cortical development.

Brain↗
PubMed2004

Effects of ethanol on cultured embryonic neurons from the cerebral cortex of the rat.

Fetal alcohol syndrome is a serious disorder that causes lifelong learning, memory, and behavioral problems. In the current study, we determined the ethanol concentrations that produced detrimental effects on the development of embryonic cortical neurons because mental capacity seems to be proportional to the level of dendritic arborization. Neurons from fetal rat cortices were grown in culture in close proximity to a glial plane. The cells were treated with concentrations of ethanol ranging from 450 nM to 45 mM, and neurite outgrowth was subsequently quantified. A significant decrease in dendritic branching was observed at ethanol concentrations as low as 45 microM after 6 days of ethanol exposure in vitro, whereas changes in primary neurite outgrowth were observed at an ethanol concentration of 4.5 microM. This finding is of particular interest as it seems to indicate that occasional ethanol exposure is detrimental to cortical development at very low concentrations of ethanol.

Animals↗
PubMed2002

Reduction of early thalamic input alters adult corticocortical connectivity.

The functional specificity of mammalian isocortex requires that precise connections be established between cortical areas and their targets. While recent studies of cortical development have focused on intrinsic specification, the role of extrinsic factors has received considerably less attention. In the present study, we examined how early removal of thalamic input affects the development of visual corticocortical connections. Hamster pups received ablations of visual thalamic nuclei on the day of birth. At 30 days of age, an injection of horseradish peroxidase (HRP) was placed into the area of cortex deafferented by the early thalamic ablation to retrogradely label adult corticocortical connections. Ablated animals displayed a significant increase in the number of corticocortical connections compared to control animals. The increased connectivity in ablated animals was primarily due to a significant increase in the number of corticocortical projections arising from non-visual areas. These results demonstrate that an intact thalamocortical projection is necessary for the development of normal cortical connectivity.

Animals↗
PubMed2005

Early asymmetry of gene transcription in embryonic human left and right cerebral cortex.

The human left and right cerebral hemispheres are anatomically and functionally asymmetric. To test whether human cortical asymmetry has a molecular basis, we studied gene expression levels between the left and right embryonic hemispheres using serial analysis of gene expression (SAGE). We identified and verified 27 differentially expressed genes, which suggests that human cortical asymmetry is accompanied by early, marked transcriptional asymmetries. LMO4 is consistently more highly expressed in the right perisylvian human cerebral cortex than in the left and is essential for cortical development in mice, suggesting that human left-right specialization reflects asymmetric cortical development at early stages.

Adaptor Proteins, Signal Transducing↗
PubMed2006

The development of cortical connections.

The cortex receives its major sensory input from the thalamus via thalamocortical axons, and cortical neurons are interconnected in complex networks by corticocortical and callosal axons. Our understanding of the mechanisms generating the circuitry that confers functional properties on cortical neurons and networks, although poor, has been advanced significantly by recent research on the molecular mechanisms of thalamocortical axonal guidance and ordering. Here we review recent advances in knowledge of how thalamocortical axons are guided and how they maintain order during that process. Several studies have shown the importance in this process of guidance molecules including Eph receptors and ephrins, members of the Wnt signalling pathway and members of a novel planar cell polarity pathway. Signalling molecules and transcription factors expressed with graded concentrations across the cortex are important in establishing cortical maps of the topography of sensory surfaces. Neural activity, both spontaneous and evoked, plays a role in refining thalamocortical connections but recent work has indicated that neural activity is less important than was previously thought for the development of some early maps. A strategy used widely in the development of corticocortical and callosal connections is the early overproduction of projections followed by selection after contact with the target structure. Here we discuss recent work in primates indicating that elimination of juvenile projections is not a major mechanism in the development of pathways feeding information forward to higher levels of cortical processing, although its use is common to developing feedback pathways.

Animals↗
PubMedDate not supplied

Orientation-specific cortical responses develop in early infancy.

Neurones in the visual cortex of higher mammals differ from those elsewhere in the visual pathway in that the majority respond selectively to particular edge or bar orientations in the stimulus. We have developed a visually evoked potential (VEP) technique which isolates the response of orientation-selective mechanisms from that of cortical or sub-cortical neurones which lack orientation selectivity. We are unable to find such orientation-selective responses in newborn human infants within the sensitivity of our method, but repeated longitudinal testing of individual infants shows that measurable responses emerge around 6 weeks of age. This result is consistent with the idea that human cortical visual function is very immature at birth, but develops rapidly in the first two postnatal months.

Age Factors↗
PubMed2007

Breaches of the pial basement membrane and disappearance of the glia limitans during development underlie the cortical lamination defect in the mouse model of muscle-eye-brain disease.

Neuronal overmigration is the underlying cellular mechanism of cerebral cortical malformations in syndromes of congenital muscular dystrophies caused by defects in O-mannosyl glycosylation. Overmigration involves multiple developmental abnormalities in the brain surface basement membrane, Cajal-Retzius cells, and radial glia. We tested the hypothesis that breaches in basement membrane and the underlying glia limitans are the key initial events of the cellular pathomechanisms by carrying out a detailed developmental study with a mouse model of muscle-eye-brain disease, mice deficient in O-mannose beta31,2-N-acetylglucosaminyltransferase 1 (POMGnT1). The pial basement membrane was normal in the knockout mouse at E11.5. It was breached during rapid cerebral cortical expansion at E13.5. Radial glial endfeet, which comprise glia limitans, grew out of the neural boundary. Neurons moved out of the neural boundary through these breaches. The overgrown radial glia and emigrated neurons disrupted the overlying pia mater. The overmigrated neurons did not participate in cortical plate (CP) development; rather they formed a diffuse cell zone (DCZ) outside the original cortical boundary. Together, the DCZ and the CP formed the knockout cerebral cortex, with disappearance of the basement membrane and the glia limitans. These results suggest that disappearance of the basement membrane and the glia limitans at the cerebral cortical surface during development underlies cortical lamination defects in congenital muscular dystrophies and a cellular mechanism of cortical malformation distinct from that of the reeler mouse, double cortex syndrome, and periventricular heterotopia.

Animals↗
PubMed1994

Development of cortical contractility in the Xenopus laevis oocyte mediated by reorganisation of the cortical cytoskeleton: a model.

As the amphibian oocyte becomes the fertilisation-competent egg an actin-myosin network assembles in the cortex which provides for the cortical contraction that accompanies fertilisation. A number of recent investigations provide data for development of a model detailing the structural changes which should accompany the development of this contractile network as well as the signalling mechanisms which regular assembly and contraction.

Actins↗
PubMed2006

The self-regulating nature of spontaneous synchronized activity in developing mouse cortical neurones.

Waves of spontaneous electrical activity that are highly synchronized across large populations of neurones occur throughout the developing mammalian central nervous system. The stages at which this activity occurs are tightly regulated to allow activity-dependent developmental programmes to be initiated correctly. What determines the onset and cessation of spontaneous synchronous activity (SSA) in a particular region of the nervous system, however, remains unclear. We have tested the hypothesis that activity itself triggers developmental changes in intrinsic and circuit properties that determine the stages at which SSA occurs. To do this we exposed cultured slices of mouse neocortex to tetrodotoxin (TTX) to block SSA, which normally occurs between embryonic day 17 (E17) and postnatal day 3 (P3). In control cultured slices, SSA rarely occurs after P3. In TTX-treated slices, however, SSA was generated from P3 (the day of TTX removal) until at least P10. This indicates that in the absence of spontaneous activity, the mechanisms that normally determine the timing of SSA are not initiated, and that a compensatory response occurs that shifts the time of SSA occurrence to later developmental stages.

Action Potentials↗
PubMed1987

Facilitation of premotor cortical seizure development by intranigral muscimol.

The role of the substantia nigra in seizure development was investigated using a chronic model of partial onset generalized seizure induced by low frequency cortical stimulation. Unilateral intranigral micro-injection of muscimol, a GABA receptor agonist, was found to facilitate partial onset seizure development, but did not affect developed seizures. This finding suggested that a non-dopaminergic, presumably GABAergic, mechanism was involved since the facilitatory effect of intranigral muscimol was not modified by haloperidol pretreatment.

Animals↗
PubMed1995

Intrauterine cocaine exposure of rabbits: persistent elevation of GABA-immunoreactive neurons in anterior cingulate cortex but not visual cortex.

The effects of prenatal cocaine exposure on the development of the rabbit cerebral cortex were studied. Two cortical areas were compared: primary visual cortex (VC) and anterior cingulate cortex (ACC). ACC was selected because behavioral deficits observed in cocaine-exposed infants suggest the involvement of ACC. In addition, ACC receives dense dopaminergic innervation and cocaine's action in inhibiting the re-uptake of dopamine is believed to underly the rewarding properties of cocaine. VC was selected as a control area because there is no evidence of behavioral deficits associated with visual perception in cocaine-exposed infants, and because VC receives minimal dopaminergic innervation. Two aspects of cortical development were studied: (i) cortical morphology, growth and cytoarchitectonic organization; and (ii) the development of the GABAergic neurotransmitter system. Measures of postnatal cortical growth, including cortical lamination, cell number and soma size, were compared in cocaine-exposed or control (saline) rabbits aged P5-P60. There was no difference between cocaine and saline animals in any of these parameters, and cortical cytoarchitecture appeared normal. However, despite the absence of major abnormalities in cortical development, we found that the number of GABA-immunoreactive neurons in cocaine-exposed animals was significantly higher than normal in ACC. This effect was highly consistent, was present in all laminae and at all ages studied, and persisted into maturity (P60). In contrast, in VC, the number of GABA-immunoreactive neurons in cocaine-exposed animals did not differ from normal. We suggest that increased GABA immunoreactivity may reflect a compensatory response to excessive excitatory input to ACC. A change in the balance of excitation and inhibition in ACC, reflecting 'noisy' or dysfunctional intracortical circuitry, may underly the emotional lability and attentional deficits characteristically described in infants exposed in utero to cocaine.

Animals↗
PubMed1979

The effect of destroying the whisker follicles in mice on the sensory nerve, the thalamocortical radiation and cortical barrel development.

Electrolytic destruction of whisker follicles in mice on the day of birth has been found to cause degeneration in the sensory nerve fibres supplying the follicles. The severity of the degeneration has been assessed in animals between 2 and 20 days old by counting the total number of myelinated fibres in the maxillary nerves on both normal and lesioned sides. The degeneration is apparent after 2 days and by 20 days the nerve on the lesioned side contains only 38% of the normal fibre content. This degeneration has also been shown to involve the trigeminal root, central to the ganglion. In addition, the lesioning procedure modifies the terminations of thalamocortical fibres in the barrel region of the sensory cortex. These terminations are normally in clusters, each corresponding to a barrel, but, after lesioning the follicles, the terminals appear to be evenly distributed in layer IV and cortical barrel structures no longer develop. In postnatal mice, electrolytic destruction of whisker follicles had less effect upon maxillary nerve fibres and cortical barrels. The number of myelinated axons surviving until day 20 increased progressively with later lesioning to reach nearly 80% of the control level when lesions were made on day 10. Cortical barrels became secure earlier than the maxillary nerve, for a normal number of cortical barrels was present at day 12 when follicles were destroyed on day 4. The implications of these results for the formation of cortical barrels is discussed.

Animals↗
PubMed2006

Postsynaptic TrkB signaling has distinct roles in spine maintenance in adult visual cortex and hippocampus.

In adult primary visual cortex (V1), dendritic spines are more persistent than during development. Brain-derived neurotrophic factor (BDNF) increases synaptic strength, and its levels rise during cortical development. We therefore asked whether postsynaptic BDNF signaling through its receptor TrkB regulates spine persistence in adult V1. This question has been difficult to address because most methods used to alter TrkB signaling in vivo affect cortical development or cannot distinguish between pre- and postsynaptic mechanisms. We circumvented these problems by employing transgenic mice expressing a dominant negative TrkB-EGFP fusion protein in sparse pyramidal neurons of the adult neocortex and hippocampus, producing a Golgi-staining-like pattern. In adult V1, expression of dominant negative TrkB-EGFP resulted in reduced mushroom spine maintenance and synaptic efficacy, accompanied by an increase in long and thin spines and filopodia. In contrast, mushroom spine maintenance was unaffected in CA1, indicating that TrkB plays fundamentally different roles in structural plasticity in these brain areas.

Animals↗