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PubMed1991

[Cervical sensitivity participates in the development of cortical coding of orientation].

Extraocular proprioceptive afferents associated with eye movements had been shown to be necessary during visual experience to allow the development of orientation selectivity in visual cortical neurons. In the present study, it has been demonstrated that cervical proprioceptive afferents were also involved in the process. Their suppression reduced the level of orientation selectivity reach after a controlled visual experience compared to the level observed in intact animals. Similarly, this suppression increased the deleterious effects of a deafferentation of eye muscles when both were associated. These results show that neck muscle proprioceptive afferents are involved in the process of development of orientation selectivity by visual cortical neurons.

Animals↗
PubMed2005

Genetics of the polymicrogyria syndromes.

Polymicrogyria is a relatively common malformation of cortical development, characterised by multiple small gyri with abnormal cortical lamination. The different forms of polymicrogyria encompass a wide range of clinical, aetiological, and histological findings. Advances in imaging have improved the diagnosis and classification of the condition. The molecular basis of polymicrogyria is beginning to be elucidated with the identification of a gene, GPR56, for bilateral frontoparietal polymicrogyria. Functional studies of the GPR56 gene product will yield insights not only into the causes of polymicrogyria but also into the mechanisms of normal cortical development and the regional patterning of the cerebral cortex. Based on imaging studies, several other region specific patterns of polymicrogyria have been identified, and there is increasing evidence that these may also have a significant genetic component to their aetiology. This paper reviews current knowledge of the different polymicrogyria syndromes, with discussion of clinical and imaging features, patterns of inheritance, currently mapped loci, candidate genes, chromosomal abnormalities, and implications for genetic counselling.

Cerebral Cortex↗
PubMed1997

Early specification and autonomous development of cortical fields in the mouse hippocampus.

Studies of the specification of distinct areas in the developing cerebral cortex have until now focused mainly on neocortex. We demonstrate that the hippocampus, an archicortical structure, offers an elegant, alternative system in which to explore cortical area specification. Individual hippocampal areas, called CA fields, display striking molecular differences in maturity. We use these distinct patterns of gene expression as markers of CA field identity, and show that the two major hippocampal fields, CA1 and CA3, are specified early in hippocampal development, during the period of neurogenesis. Two field-specific markers display consistent patterns of expression from the embryo to the adult. Presumptive CA1 and CA3 fields (Pca1, Pca3) can therefore be identified between embryonic days 14.5 and 15.5 in the mouse, a week before the fields are morphologically distinct. No other individual cortical areas have been detected by gene expression as early in development. Indeed, other features that distinguish between the CA fields appear after birth, indicating that mature CA field identity is acquired over at least 3 weeks. To determine if Pca1 and Pca3 are already specified to acquire mature CA field identities, the embryonic fields were isolated from further potential specification cues by maintaining them in slice culture. CA field development proceeds in slices of the entire embryonic hippocampus. More strikingly, slices restricted to Pca1 or Pca3 alone also develop appropriate mature features of CA1 or CA3. Pca1 and Pca3 are therefore able to develop complex characteristics of mature CA field identity autonomously, that is, without contact or innervation from other fields or other parts of the brain. Because Pca1 and Pca3 can be identified before major afferents grow into the hippocampus, innervation may also be unnecessary for the initial division of the hippocampus into separate fields. Providing a clue to the source of the true specifying signals, the earliest field markers appear first at the poles of the hippocampus, then progress inwards. General hippocampal development does not follow this pronounced pattern. We suggest that the sources of signals that specify hippocampal field identity lie close to the hippocampal poles, and that the signals operate first on cells at the poles, then move inwards.

Animals↗
PubMed2002

Asymmetric Numb distribution is critical for asymmetric cell division of mouse cerebral cortical stem cells and neuroblasts.

Stem cells and neuroblasts derived from mouse embryos undergo repeated asymmetric cell divisions, generating neural lineage trees similar to those of invertebrates. In Drosophila, unequal distribution of Numb protein during mitosis produces asymmetric cell divisions and consequently diverse neural cell fates. We investigated whether a mouse homologue m-numb had a similar role during mouse cortical development. Progenitor cells isolated from the embryonic mouse cortex were followed as they underwent their next cell division in vitro. Numb distribution was predominantly asymmetric during asymmetric cell divisions yielding a beta-tubulin III(-) progenitor and a beta-tubulin III(+) neuronal cell (P/N divisions) and predominantly symmetric during divisions producing two neurons (N/N divisions). Cells from the numb knockout mouse underwent significantly fewer asymmetric P/N divisions compared to wild type, indicating a causal role for Numb. When progenitor cells derived from early (E10) cortex undergo P/N divisions, both daughters express the progenitor marker Nestin, indicating their immature state, and Numb segregates into the P or N daughter with similar frequency. In contrast, when progenitor cells derived from later E13 cortex (during active neurogenesis in vivo) undergo P/N divisions they produce a Nestin(+) progenitor and a Nestin(-) neuronal daughter, and Numb segregates preferentially into the neuronal daughter. Thus during mouse cortical neurogenesis, as in Drosophila neurogenesis, asymmetric segregation of Numb could inhibit Notch activity in one daughter to induce neuronal differentiation. At terminal divisions generating two neurons, Numb was symmetrically distributed in approximately 80% of pairs and asymmetrically in 20%. We found a significant association between Numb distribution and morphology: most sisters of neuron pairs with symmetric Numb were similar and most with asymmetric Numb were different. Developing cortical neurons with Numb had longer processes than those without. Numb is expressed by neuroblasts and stem cells and can be asymmetrically segregated by both. These data indicate Numb has an important role in generating asymmetric cell divisions and diverse cell fates during mouse cortical development.

Animals↗
PubMed1977

Development of cortical spreading depression and of its transition to the caudate nucleus in rats.

The development of Leão's spreading depression (SD) of electroencephalographic activity was studied in young rats by recording the accompanying slow potential changes (SPC). The propagation rate of cortical SD increased from 1.65 mm/min on Day 15 to 2.6 mm/min on Day 20; the increase of SPC amplitude and the decrease of SPC duration were less evident over the same period. The SD elicited in the caudate nucleus by microinjections of KCl did not spread to neocortex in 20- and 30-day-old rats and transition occurred in only 5% of KCl applications in 40-day-old rats. Application of a pyrrolopyrimidine derivative (BW 57-271; 5 mg/kg) increased the cortico-caudate SD transition of 100% in rats aged 20 days or older and increased the SPC amplitude in both structures. The development of SD parameters can be ascribed to dendritic growth and to the decrease of extracellular space; the cortico-caudate propagation block can be ascribed to morphological immaturity of the transitional zone.

Age Factors↗
PubMed2002

The role of reelin in the development and evolution of the cerebral cortex.

Reelin is an extracellular matrix protein that is defective in reeler mutant mice and plays a key role in the organization of architectonic patterns, particularly in the cerebral cortex. In mammals, a "reelin signal" is activated when reelin, secreted by Cajal-Retzius neurons, binds to receptors of the lipoprotein receptor family on the surface of cortical plate cells, and triggers Dab1 phosphorylation. As reelin is a key component of cortical development in mammals, comparative embryological studies of reelin expression were carried out during cortical development in non-mammalian amniotes (turtles, squamates, birds and crocodiles) in order to assess the putative role of reelin during cortical evolution. The data show that reelin is present in the cortical marginal zone in all amniotes, and suggest that reelin has been implicated in the evolution of the radial organization of the cortical plate in the synapsid lineage leading from stem amniotes to mammals, as well as in the lineage leading to squamates, thus providing an example of homoplastic evolution (evolutionary convergence). The mechanisms by which reelin instructs radial cortical organization in these two lineages seem different: in the synapsid lineage, a drastic amplification of reelin production occurred in Cajal-Retzius cells, whereas in squamates, in addition to reelin-secreting cells in the marginal zone, a second layer of reelin-producing cells developed in the subcortex. Altogether, our results suggest that the reelin-signaling pathway has played a significant role in shaping the evolution of cortical development.

Animals↗
PubMed1986

Neurotransmitter changes during development of cortical neuronal cultures.

Benzodiazepine (BDZ) ligands clonazepam (CLO) and Ro5-4864 which preferentially bind to neuronal and non-neuronal elements, respectively, have been used to follow neuronal and non-neuronal development in fetal murine cortical cultures. CLO-displaceable BDZ binding, choline acetyltransferase (CAT) activity, high-affinity delta-aminobutyric acid (GABA) uptake, and glutamic acid decarboxylase (GAD) activity reached a maximum value at the end of the second week in culture reflecting maximum neuronal maturation and development. There is a developmental order of these four functions: CAT activity (main enzyme in the synthesis of acetylcholine, a stimulating neurotransmitter) reached maximal levels first, 3H-GABA uptake and CLO-displaceable flunitrazepam receptor binding reached maximal levels 1 day later, and 4 days later GAD activity (primary enzyme in the synthesis of GABA, an inhibitor neurotransmitter) reached maximal levels.

Animals↗
PubMed2002

Influence of radial glia and Cajal-Retzius cells in neuronal migration.

Normal development of cerebral cortex depends on proper sequential genesis of cortical neurons and glia. Disruption of corticogenesis in ferret by short-term arresting of cell division using injections of methylazoxy methanol (MAM) leads to a specific constellation of effects, including disruption and early differentiation of radial glia into astrocytes and disorganization of reelin-containing Cajal-Retzius cells. We hypothesize that early interference of normal cortical development removes a factor instrumental in maintaining radial glia in their normal elongated shape. In support of this idea, coculture of MAM-treated slices with normal cortical plate restores radial glia and Cajal-Retzius cells to their normal positions. Recently, we found that conditioned medium obtained from normal organotypic cultures returned radial glia toward their normal morphology only in a fraction of 30-50 kDa molecular weight (MW). To assess whether restoring this factor would also improve effective migration into the cortical plate of E24 MAM-treated animals, we conducted experiments using cocultures of normal cortical plate with organotypic cultures of MAM-treated cortex, which received prior BrdU injections. In both the normal and E24 MAM-treated/normal cortical plate coculture, a greater percentage of BrdU positive cells migrated effectively into the cortical plate. We suggest that early interruption of cell division eliminates a population of cells and a factor important for maintaining proper cortical development, specifically providing cues maintaining elongation of radial glia.

Animals↗
PubMed2005

Soluble CPG15 expressed during early development rescues cortical progenitors from apoptosis.

The balance between proliferation and apoptosis is critical for proper development of the nervous system. Yet, little is known about molecules that regulate apoptosis of proliferative neurons. Here we identify a soluble, secreted form of CPG15 expressed in embryonic rat brain regions undergoing rapid proliferation and apoptosis, and show that it protects cultured cortical neurons from apoptosis by preventing activation of caspase 3. Using a lentivirus-delivered small hairpin RNA, we demonstrate that endogenous CPG15 is essential for the survival of undifferentiated cortical progenitors in vitro and in vivo. We further show that CPG15 overexpression in vivo expands the progenitor pool by preventing apoptosis, resulting in an enlarged, indented cortical plate and cellular heterotopias within the ventricular zone, similar to the phenotypes of mutant mice with supernumerary forebrain progenitors. CPG15 expressed during mammalian forebrain morphogenesis may help balance neuronal number by countering apoptosis in specific neuroblasts subpopulations, thus influencing final brain size and shape.

Animals↗
PubMed2006

Role of mechanical factors in the morphology of the primate cerebral cortex.

The convoluted cortex of primates is instantly recognizable in its principal morphologic features, yet puzzling in its complex finer structure. Various hypotheses have been proposed about the mechanisms of its formation. Based on the analysis of databases of quantitative architectonic and connection data for primate prefrontal cortices, we offer support for the hypothesis that tension exerted by corticocortical connections is a significant factor in shaping the cerebral cortical landscape. Moreover, forces generated by cortical folding influence laminar morphology, and appear to have a previously unsuspected impact on cellular migration during cortical development. The evidence for a significant role of mechanical factors in cortical morphology opens the possibility of constructing computational models of cortical development based on physical principles. Such models are particularly relevant for understanding the relationship of cortical morphology to the connectivity of normal brains, and structurally altered brains in diseases of developmental origin, such as schizophrenia and autism.

Algorithms↗
PubMed2006

Cyclooxygenase-2 mediates the development of cortical spreading depression-induced tolerance to transient focal cerebral ischemia in rats.

We examined the role of cyclooxygenase-2 in the development of ischemic tolerance induced by cortical spreading depression against transient, focal brain ischemia. Cortical spreading depression was continuously induced for 2 h with topical KCl (13+/-1 depolarizations/2 h) in male Wistar rats. At 1, 2, 3, 4, and 5 days following recovery, the middle cerebral artery was transiently occluded for 120 min. Four days later, the animals were killed and infarct volume was determined. Additionally, cyclooxygenase-2 levels in the cerebral cortex and 15 deoxy-Delta(12, 14) PGJ2 levels in cerebrospinal fluid were determined at these times with Western blotting and immunoassay, respectively. Infarct volume was reduced compared with non-cortical spreading depression control animals (274.3+/-15.3 mm3) when cortical spreading depression was performed 3 and 4 days before middle cerebral artery occlusion (163.9+/-14.2 mm3, 154.9+/-14.2 mm3) but not at 1, 2 and 5 days (280.4+/-17.3 mm3, 276.3+/-16.9 mm3 and 268.5+/-17.3 mm3). Cyclooxygenase-2 levels increased most dramatically starting at 2 days, peaked at 3 days, and started to return toward baseline at 4 days after cortical spreading depression. 15 Deoxy-Delta(12, 14) PGJ2 levels increased from 134.7+/-83 pg/ml at baseline to 718+/-98 pg/ml at 3 days. Administration of N-[2-cyclohexyloxy-4-nitrophenyl] methanesulphonamide (10 mg/kg, i.v.), a selective cyclooxygenase-2 inhibitor, at 1 h prior to middle cerebral artery occlusion in cortical spreading depression preconditioned animals did not affect infarct volume (162.6+/-62.1 mm3). However, administration of N-[2-cyclohexyloxy-4-nitrophenyl] methanesulphonamide given three times prior to middle cerebral artery occlusion prevented the reduced infarct volume induced by cortical spreading depression preconditioning (272.9+/-63.2 mm3). Administration of L-nitro-arginine methyl ester (4 mg/kg, i.v.) prior to cortical spreading depression blocked increases in cyclooxygenase-2 normally seen at 3 and 4 days. We conclude that NO-mediated cyclooxygenase-2 upregulation by cortical spreading depression protects the brain against ischemic damage.

Animals↗
PubMed2004

HGF regulates the development of cortical pyramidal dendrites.

Although hepatocyte growth factor (HGF) and its receptor tyrosine kinase MET are widely expressed in the developing and mature central nervous system, little is known about the role of MET signaling in the brain. We have used particle-mediated gene transfer in cortical organotypic slice cultures established from early postnatal mice to study the effects of HGF on the development of dendritic arbors of pyramidal neurons. Compared with untreated control cultures, exogenous HGF promoted a highly significant increase in dendritic growth and branching of layer 2 pyramidal neurons, whereas inactivation of endogenous HGF with function-blocking, anti-HGF antibody caused a marked reduction in size and complexity of the dendritic arbors of these neurons. Furthermore, pyramidal neurons transfected with an MET dominant-negative mutant receptor likewise had much smaller and less complex dendritic arbors than did control transfected neurons. Our results indicate that HGF plays a role in regulating dendritic morphology in the developing cerebral cortex.

Animals↗
PubMed2002

Development of cortical and subcortical brain structures in childhood and adolescence: a structural MRI study.

The purpose of the present study was to describe in greater anatomical detail the changes in brain structure that occur during maturation between childhood and adolescence. High-resolution MRI, tissue classification, and anatomical segmentation of cortical and subcortical regions were used in a sample of 35 normally developing children and adolescents between 7 and 16 years of age (mean age 11 years; 20 males, 15 females). Each cortical and subcortical measure was examined for age and sex effects on raw volumes and on the measures as proportions of total supratentorial cranial volume. Results indicate age-related increases in total supratentorial cranial volume and raw and proportional increases in total cerebral white matter. Gray-matter volume reductions were only observed once variance in total brain size was proportionally controlled. The change in total cerebral white-matter proportion was significantly greater than the change in total cerebral gray-matter proportion over this age range, suggesting that the relative gray-matter reduction is probably due to significant increases in white matter. Total raw cerebral CSF volume increases were also observed. Within the cerebrum, regional patterns varied depending on the tissue (or CSF) assessed. Only frontal and parietal cortices showed changes in gray matter, white matter, and CSF measures. Once the approximately 7% larger brain volume in males was controlled, only mesial temporal cortex, caudate, thalamus, and basomesial diencephalic structures showed sex effects with the females having greater relative volumes in these regions than the males. Overall, these results are consistent with earlier reports and describe in greater detail the regional pattern of age-related differences in gray and white matter in normally developing children and adolescents.

Adolescent↗
PubMed2002

Regulation of cortical dendrite development by Slit-Robo interactions.

Slit proteins have previously been shown to regulate axon guidance, branching, and neural migration. Here we report that, in addition to acting as a chemorepellant for cortical axons, Slit1 regulates dendritic development. Slit1 is expressed in the developing cortex, and exposure to Slit1 leads to increased dendritic growth and branching. Conversely, inhibition of Slit-Robo interactions by Robo-Fc fusion proteins or by a dominant-negative Robo attenuates dendritic branching. Stimulation of neurons transfected with a Met-Robo chimeric receptor with Hepatocyte growth factor leads to a robust induction of dendritic growth and branching, suggesting that Robo-mediated signaling is sufficient to induce dendritic remodeling. These experiments indicate that Slit-Robo interactions may exert a significant influence over the specification of cortical neuron morphology by regulating both axon guidance and dendritic patterning.

Animals↗
PubMed1985

Development of cortical polarity in mouse eggs: involvement of the meiotic apparatus.

Experiments were carried out to determine the origin of cortical polarity in mouse eggs and its possible relation to the meiotic apparatus. Cortices of mature eggs overlying the meiotic apparatus (microvillus-free area) were distinguished by an absence of microvilli and a thickened layer of actin. In contrast, the surfaces of immature oocytes were covered entirely with a dense population of microvilli and were subtended by a uniform layer of actin. When induced to undergo maturation, meiotic spindles formed in the center of immature oocytes and then moved peripherally. Coincident with the cortical localization of the meiotic spindle was the formation of a microvillus-free area, i.e., a loss of microvilli and a thickening of the actin layer associated with this region of the egg cortex. If immature oocytes were incubated in cytochalasin B, meiotic spindles formed; however, they failed to move peripherally and microvillus-free areas did not develop. Oocytes incubated in colchicine did not form meiotic spindles, although the chromosomes condensed and became localized to cortices where microvillus-free areas developed. Cytochalasin B-treated mature eggs maintained intact meiotic spindles and exhibited a disappearance of microvillus-free areas and a reduction in cortical actin. The chromosomes of mature eggs treated with colchicine remained associated with microvillus-free areas despite the disappearance of meiotic spindles. Occasionally, colchicine-treated eggs possessed more than one cortically located mass of chromosomes, each of which was associated with a microvillus-free area. These observations indicate that mechanisms involving the movement of the meiotic spindle to the oocyte cortex and development and maintenance of cortical polarity are cytochalasin B sensitive. Commensurate with the localization of meiotic chromosomes to the egg cortex is the reorganization of cortical actin and the formation of a microvillus-free area.

Animals↗
PubMed1999

Cortical maturation in normal and abnormal fetuses as assessed with prenatal MR imaging.

PURPOSE: To establish the appearance of normal fetal cortical development in utero and compare it with the appearance of abnormal cortical development. MATERIALS AND METHODS: Magnetic resonance (MR) images of the brain in 53 normal and 40 abnormal fetuses at 14-38 weeks gestational age (GA) were reviewed. The GAs at the time of MR imaging visualization of the fissures or sulci were compared with the GA guidelines based on neuroanatomic studies. RESULTS: In normal fetuses, the sulcation landmarks appeared on MR images in the order predicted by using anatomic studies, with a 0-8-week lag in the MR imaging visualization of the sulci compared with the reported time of visualization of the sulci in anatomic specimens. When landmarks were grouped by range of GAs, the expected MR imaging sulcation landmarks in the group with younger GAs than the actual GA were seen in 50 of 53 (94%) normal fetuses, in five of nine fetuses (56%, P < .05) with isolated mild ventriculomegaly, and in 24 of 31 fetuses (77%, P < .05) with other CNS anomalies. CONCLUSION: Normal fetal cortical maturation at MR imaging follows a predictable course that is slightly delayed compared with that described in neuroanatomic specimens. This maturation is often further delayed in fetuses with CNS abnormalities.

Agenesis of Corpus Callosum↗
PubMed1993

Synaptophysin immunohistochemistry reveals inside-out pattern of early synaptogenesis in ferret cerebral cortex.

Synaptogenesis in the ferret cerebral cortex was examined from the day of birth to adulthood with an antibody against synaptophysin at the light and electron microscopic levels. Due to the premature birth of ferrets, the generation of cells destined to the upper cortical layers and their subsequent migration to their final positions in the cortical plate are largely postnatal events. Throughout the newborn ferret cerebral cortex, a high amount of synaptophysin immunoreactivity was present within the marginal zone and subplate region. Staining was also conspicuous within the forming cortical plate. The typical layering pattern of synaptophysin immunoreactivity in the developing cortical plate correlated with the migration pattern of cortical neurons. The synaptic density was lowest directly below the marginal zone, where the youngest neurons just stopped their migration. Below this zone, the density of the synaptic staining increased gradually toward lower (and older) cortical plate layers. As the cortex expanded, the synaptophysin immunoreactivity pattern closely followed the expansion, suggesting that synapses were formed in a given layer shortly after the cells migrating to this layer reached their final position. As soon as cell migration had finished, the entire cortical plate contained dense synaptophysin immunoreactivity, in a pattern similar to that observed in the adult animal. During cortical development, a rostrocaudal and a laterodorsal gradient of synaptogenesis was observed. At any given time, rostral and lateral regions of the cerebral cortex were more advanced in their development than caudal and dorsal regions. Electron microscopic examination of synaptophysin immunoreactivity in the developing cerebral cortex of ferrets confirmed that labeling was solely associated with synaptic vesicles. These vesicles were typically, but not exclusively, confined to synaptic boutons. Especially around the end of the first postnatal week, long fiber profiles loaded with synaptic vesicles were occasionally detected. As some of these fibers also showed en passant synapses along their course, we concluded that synaptic vesicle labeling may be reliably used to study synaptogenesis at the light microscopic level. A systematic analysis of samples from postnatal days 0 and 7 corroborated this conclusion, showing that synaptic profile distribution completely matched the distribution of synaptophysin immunoreactivity seen in the light microscope. In conclusion, synaptogenesis begins as soon as migratory cells reach their final position in the cortical plate. As long as cell migration continues, synaptogenesis is under the constraints of neurogenesis, following its gradients.

Aging↗