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PubMed1996

Regional cerebral glucose metabolism and postmortem pathology in Alzheimer's disease.

In four patients with an antemortem diagnosis of probable Alzheimer's disease (AD) regional cerebral glucose metabolism (rCMRGl) was studied prospectively by positron emission tomography (PET) and compared with postmortem semiquantitative neuropathology. The interval between the last PET study and autopsy was 1.3 +/- 0.8 years. In comparison with age-matched controls, the AD patients showed predominant temporoparietal hypometabolism spreading to other cortical and subcortical regions during serial PET scans. All patients had neuropathological findings typical for AD. There was a significant relationship between rCMRGl and density of senile plaques (SP) in one patient (tau b = -0.86, P < 0.05). SP were distributed quite homogeneously in all regions examined. Neurofibrillary tangles (NFT) were concentrated focally in the hippocampus-amygdala-entorhinal complex. In the context of widespread developing cortical hypometabolism, the predilection of NFT for involvement in limbic areas suggests a disruption of projection neurons as the pathogenetic process of cortical dysfunction.

Aged↗
PubMed2005

Novel function of neuronal PAS domain protein 1 in erythropoietin expression in neuronal cells.

The basic helix loop helix-PAS (bHLH-PAS) transcription factors have diverse roles in physiologic responses to the environment and in early development. One bHLH-PAS protein, neuronal PAS domain protein 1 (NPAS1), is reported to be expressed only in the central nervous system beginning at the late embryonic stage, but its function is unknown. Using an anti-NPAS1 antibody, we have shown that NPAS1 expression in cerebral cortex was observed first around embryonic Day 16.5 (E16.5) and was then dispersed throughout the region as cortical development progressed. From the similarity with hypoxia-inducible factor-1alpha (HIF-1alpha), we investigated whether NPAS1 regulates transcription of erythropoietin (EPO), which is the target of HIF-1alpha and is expressed in the brain during the early developmental stage. In the present study, we have shown that NPAS1 binds to the enhancer region of Epo in vivo. A luciferase reporter assay revealed a repressive effect of NPAS1 on hypoxia-responsive element-regulated gene expression. These results raise the possibility that NPAS1 plays a role in late central nervous system development by modulating EPO expression in response to cellular oxygen level.

Animals↗
PubMed2000

Neonatal 5,7-DHT lesions cause sex-specific changes in mouse cortical morphogenesis.

Both monoaminergic and cholinergic afferent projections to the neocortex putatively modulate cortical morphogenesis and plasticity. Previously we showed that neonatal electrolytic lesions of the cholinergic nucleus basalis magnocellularis (nBM) projections to the neocortex result in significant decreases of cortical layer width that correlate with cognitive alterations. Such electrolytic lesions, performed for lack of a selective neurotoxin in mice, may affect mono-aminergic fibers of passage. Here, we investigate the effects of neonatal 5,7 dihydroxytryptamine (5,7-DHT) focal injections into the nBM region on cortical laminar morphology in adult male and female mice. 5,7-DHT lesions on the first postnatal day resulted in significant cortical depletion of both serotonin and norepinephrine that attenuated with age. Generally, cortical layer widths increased in response to the lesion; the effects were layer, region, and sex specific. Previous reports from our laboratories described long-term behavioral alterations after comparable focal, neonatal 5,7-DHT lesions. The studies described here provide an anatomical basis for such behavioral alterations. Our data suggest that monoaminergic and cholinergic projections to the cortex may have opposite effects on the developing cortical neuropil. Jointly, our morphological and behavioral findings may have important implications for a variety of developmental disorders in humans and provide some insights into sex differences in the penetrance of these disorders.

5,7-Dihydroxytryptamine↗
PubMed1983

Development of orientation columns in cat striate cortex revealed by 2-deoxyglucose autoradiography.

In the striate cortex of adult monkeys and cats, both electrophysiology1-3 and the 2-deoxyglucose autoradiographic technique of Sokoloff4-8 suggest that neurones are arranged in functional columns or slabs that run through the full thickness of the cortex, each column containing cells with a preference for a particular orientation of line or edge in the visual field. There is disagreement, however, concerning the organization of visual cortex in very young animals and the role of visual experience in cortical development. Orientation-selective neurones clearly exist in immature cat cortex, but reports differ on their frequency, angular selectivity and degree of columnar organization (see ref. 9 for review). We have used 2-deoxyglucose autoradiography to investigate the development of cat striate cortex. This technique reveals the spatial distribution of activity in populations of neurones and should therefore provide information about how the columnar pattern develops and whether its maturation depends on visual stimulation. We report here that in normal animals, periodic metabolic labelling around layer IV was first clearly observed at 21 days of age and by 35 days the pattern had become truly columnar; in a matched series of animals deprived of normal pattern vision no differential label was observed except for weak periodicity in a single 35-day-old animal. These results suggest that cat striate cortex is immature at the time of eye-opening and that visual experience is crucial for normal maturation.

Age Factors↗
PubMed2001

Radial glia development in the mouse olfactory bulb.

Radial glia are critical for cell migration and lamination of the cortex. In most developing cortical structures, radial glia, as their name suggests, extend processes from the ventricle to the pia in regular parallel arrangements. However, immunohistochemical labeling from several laboratories suggests that radial glia have a more branched morphology in the olfactory bulb. To investigate the morphology of radial glia in the mouse olfactory bulb we (1) labeled radial glia and olfactory receptor neuron axons at 24-hour intervals by immunohistochemistry; and (2) developed a novel method of generating and applying "nanocrystals" of 1,1'-dioctadecyl-3,3,3',3'- tetramethylindocarbocyanine perchlorate (DiI) to the ventricle surface such that the processes of single olfactory bulb radial glia are labeled in the embryonic olfactory bulb. We examined the structure and interactions of radial glia with ingrowing olfactory receptor neuron (ORN) axons in late embryonic olfactory bulb development. These results showed that olfactory bulb radial glia do not form straight parallel structures as do radial glia in the neocortex but rather have a convoluted trajectory from the ventricle to the bulb surface. Moreover, olfactory bulb radial glia consistently extend tangential branches at the level of the internal plexiform layer. Beginning at embryonic day 17.5, two types of radial glia can be distinguished: type I radial glia have a process that extends from the ventricle into the glomerular layer. These apical processes form highly restricted tufts, or "glial glomeruli" at the same time that ORN axons are forming "axonal glomeruli." In type II radial glia the apical process does not enter the glomerular layer but instead ramifies within the external plexiform layer. The tight spatiotemporal relationship between the glomerulization of radial glia processes and ORN axons during development suggest that radial glia processes could play a role in the formation and/or stabilization of mammalian glomeruli.

Animals↗
PubMed2026

3D epigenome of glial cell types in developing human cortex.

The human cortex is complex and heterogeneous, undergoing extensive expansion during development1,2. Our&#xa0;prior study of neurogenesis, including radial glia (RG), intermediate progenitor cells, excitatory neurons and interneurons demonstrated that chromatin looping underlies transcriptional regulation for lineage-specific genes, shedding light on how non-coding genetic variants contribute to neuropsychiatric disorders by means of cell-type-specific gene regulation3. RG have a crucial role in generating cellular diversity through both neurogenesis and gliogenesis and can be further classified into ventricular RG (vRG) and outer RG (oRG)4,5. Given their significance in cortical development, we conducted a comprehensive three-dimensional (3D) epigenomic analysis of four main glial populations, including vRG, oRG, oligodendrocyte precursor cells and microglia, from the mid-gestational human neocortex. By integrating gene expression, chromatin accessibility, DNA methylation and 3D chromatin interactions, we identified cell-type-specific candidate cis-regulatory elements (cCREs) and validated their regulatory function using transgenic mouse embryos. Using machine learning, we prioritized 112 schizophrenia risk variants within glia cCREs and further confirmed the predicted vRG enhancer disruption by&#xa0;the rs4449074 risk allele in vivo. Finally, oRG cCREs are enriched for human accelerated regions compared with other cCREs and a subset of human accelerated regions show activity differences from their chimpanzee orthologues that interact with genes involved in neuronal development. Our findings advance the understanding of human-specific gene regulation during corticogenesis.

Journal Article↗
PubMed1997

Regulation of the polysialylated form of the neural cell adhesion molecule in the developing striatum: effects of cortical lesions.

Early in development, the polysialylated form of the neural cell adhesion molecule (PSA-NCAM) is expressed by growth cones, neuronal processes, and neuronal cell bodies. In rat striatum, PSA-NCAM expression becomes progressively restricted to pre- and postsynaptic membranes and is undetectable by postnatal day 25 (P25), i.e., after corticostriatal synaptogenesis. This study examined the effects of cortical lesions performed on P14, when the corticostriatal projection is already primarily unilateral and cortical inputs have not yet formed asymmetric synapses on striatal neurons. Rats were killed on P25, and PSA-NCAM expression was examined by immunoblotting and immunohistochemistry with light and electron microscopy. In contrast to the case in controls, PSA-NCAM expression was maintained in the striatum of lesioned pups. Ultrastructural studies showed that PSA-NCAM was present 1) in growth cone-like structures and neuronal processes and 2) in striatal neurons. Together with the presence of growth cones, the observation that the number of asymmetric synapses was unchanged in the denervated striatum suggests that axonal sprouting occurred in response to the lesion. This was confirmed by axonal labeling in the denervated striatum after injection of Fluoro-Ruby in the contralateral cortex. The data indicate that P14 cortical lesions affect PSA-NCAM expression in the developing striatum 1) by inducing a robust axonal plasticity resulting in the presence of immature presynaptic elements that contain PSA-NCAM and 2) by delaying the loss of PSA-NCAM expression in striatal neurons, suggesting that the lesion affects the time course of striatal maturation.

Aging↗
PubMed1999

Brain responses reveal the learning of foreign language phonemes.

Learning to speak a new language requires the formation of recognition patterns for the speech sounds specific to the newly acquired language. The present study demonstrates the dynamic nature of cortical memory representations for phonemes in adults by using the mismatch negativity (MMN) event-related potential. We studied Hungarian and Finnish subjects, dividing the Hungarians into a naive (no knowledge of Finnish) and a fluent (in Finnish) group. We found that the MMN for a contrast between two Finnish phonemes was elicited in the fluent Hungarians but not in the naive Hungarians. This result indicates that the fluent Hungarians developed cortical memory representations for the Finnish phoneme system that enabled them to preattentively categorize phonemes specific to this language.

Adult↗
PubMed1984

Effects of early tamoxifen treatment on hormonal content of 15-day quail embryo gonads.

An early treatment of quail eggs with an antiestrogen (Tamoxifen = TAM) modifies the female gonads morphologically. In the left ovary, the proliferation of the germinal epithelium and formation of a cortex is markedly inhibited, while the medulla on both sides becomes more developed and keeps a cordal organization. The effects of TAM on the hormonal potentialities of 15-day embryo gonads have been investigated by radioimmunoassay. The data have been compared with those of normal gonads. The results indicate that the TAM treatment does not mainly modify the hormonal levels and patterns in the gonads of both sexes and does not inhibit the function of the hypothalamo-hypophyseal-gonadal axis. The reduced cortical development is thus not linked to an estrogen decrease but to competitive effects on receptors at the level of this tissue.

Animals↗
PubMed1977

Maturation of evoked climbing fiber input to rat cerebellar purkinje cells (I.).

An analysis of evoked responses of Purkinje cells in developing rat cerebellum to climbing fiber input was conducted to determine which identifying properties of this afferent system are established early in development and which specific features mature with age. Rat pups at various ages were anesthetized with 0.5% halothane and unit recordings made with glass micropipettes. By the third postnatal day, electrical stimulation of the sensorimotor cortex and limbs at low stimulation rates (less than 1/sec) could elicit distinct burst responses appearing at long latencies (180 msec), indicating that pathways of both ascending and descending climbing fiber systems are intact early in cerebellar cortical development. A distinctive feature maturing over the first 1-1.5 weeks was the characteristic of the all-or-none burst response since before about day 11 the interspike interval, amount of inactivation, and number of spikes in evoked burst responses all varied from stimulation to stimulation. Mean latencies decreased from 180 msec at dat 3 to 50 msec by day 10, but did not achieve the adult value of 20 msec until the fourth week. Typically, climbing fiber responses could only follow at stimulation rates of less than 0.2/sec at day 3, but by day 12 could follow up to 10/sec, which is the same as in the adult. The data indicate that the climbing fiber system establishes connectivity from diverse sources and exhibits identifying characteristics similar to the adult early in cerebellar development. Most aspects of the maturation of transmission can be explained if there were a decrease in the time scale of function of the synapses involved, mainly those in the inferior olive.

Afferent Pathways↗
PubMed2003

Presynaptic proteins in the prefrontal cortex of patients with schizophrenia and rats with abnormal prefrontal development.

Dysfunction of the prefrontal cortex in schizophrenia may be associated with abnormalities in synaptic structure and/or function and reflected in altered concentrations of proteins in presynaptic terminals and involved in synaptic plasticity (synaptobrevin/ vesicle-associated membrane protein (VAMP), synaptosomal-associated protein-25 (SNAP-25), syntaxin, synaptophysin and growth-associated protein-43 (GAP-43)). We examined the immunoreactivity of these synapse-associated proteins via quantitative immunoblotting in the prefrontal cortex of patients with schizophrenia (n=18) and in normal controls (n=23). We also tested the stability of these proteins across successive post-mortem intervals in rat brains (at 0, 3, 12, 24, 48, and 70 h). To investigate whether experimental manipulation of prefrontal cortical development in the rat alters prefrontal synaptic protein levels, we lesioned the ventral hippocampus of rats on postnatal day 7 and measured immunoreactivity of presynaptic proteins in the prefrontal cortex on postnatal day 70. VAMP immunoreactivity was lower in the schizophrenic patients by 22% (P<0.03). There were no differences in the immunoreactivity of any other proteins measured in schizophrenic patients as compared to the matched controls. Proteins were fairly stable up to 24 h and thereafter the abundance of most proteins examined was significantly reduced (falling to as low as 20% of baseline levels at 48-70 h). VAMP immunoreactivity was higher in the lesioned rats as compared to sham controls by 22% (P&<0.03). There were no significant differences between the lesioned rats and sham animals in any other presynaptic protein. These data suggest that apparently profound prefrontal cortical dysfunction in schizophrenia, as well as in an animal model of schizophrenia, may exist without gross changes in the abundance of many synaptic proteins but discrete changes in selected presynaptic molecules may be present.

Adolescent↗
PubMed1989

Cingulate sulcus development in preterm infants.

Cranial ultrasounds performed during the first 3 d of life on 211 infants of 24 to 40 wk gestational age were examined to determine the in utero development of the cingulate sulcus. The sulcus was identified between 24 and 28 wk of gestational age as fragmented echoes in the region between the thalamus and the anterior fontanelle. Over the next several weeks, these fragments coalesced into a single linear echo. Branches then appeared off of the primary cingulate sulcus, increasing in number until a complex pattern of branching was noted near term gestation. This maturational sequence was similar to postnatal cortical development determined from serial ultrasounds performed on 144 infants who were less than or equal to 32 wk of gestational age at birth. The timing of postconceptional cingulate sulcus development was independent of gestational age at birth. However, severe brain insult, defined as intraventricular hemorrhage complicated by ventriculomegaly or intraparenchymal extension or periventricular leukomalacia, was associated with significant delays in all stages of cingulate sulcus development. Cranial ultrasound examinations in preterm infants allow a noninvasive means of staging qualitative brain development during the early postnatal period.

Age Factors↗
PubMed1997

Developmental and sensory-dependent changes of phosphoinositide-linked metabotropic glutamate receptors.

Metabotropic glutamate receptors (mGluRs) can modulate synaptic transmission, and there is evidence that phosphoinositide (PI)-linked mGluRs may be involved in sensory-dependent plasticity during the development of cat visual cortex. Consequently, we asked the questions: Where are the PI-linked mGluRs (mGluR1alpha and mGluR5) in the visual cortex? Does the quantity and distribution of these receptors change in the cat visual cortex during postnatal development, and are these features sensory-dependent? We found that the quantity of mGluR1alpha decreases with age, whereas the laminar distribution of mGluR1alpha remains the same. Quantity of mGluR5 also decreases, but the laminar distribution of mGluR5 changes during development. The pattern and timing of the mGluR5 change in distribution follow the development of geniculocortical afferents. Immunostaining indicates that reduction of receptor occurs mainly in layers V-VI for mGluR1alpha and outside layer IV for mGluR5. Dark-rearing postpones the laminar change of mGluR5 and produces an increased level of mGluR5 between postnatal 1.5-6 weeks of age but has no significant effect on the mGluR1alpha distribution or the mGluR1alpha quantity. These results suggest that mGluR1alpha and mGluR5 are involved in different aspects of cortical development. The mGluR5 is more likely to be involved in sensory-dependent events than mGluR1alpha. The lack of developmental correlation between mGluR quantities and the critical period for ocular dominance plasticity also suggests that other factors besides mGluR quantities are important for ocular dominance plasticity.

Aging↗
PubMed2006

Segmentation of focal cortical dysplasia lesions on MRI using level set evolution.

Focal cortical dysplasia (FCD) is the most frequent malformation of cortical development in patients with medically intractable epilepsy. On MRI, FCD lesions are not easily differentiable from the normal cortex and defining their spatial extent is challenging. In this paper, we introduce a method to segment FCD lesions on T1-weighted MRI. It relies on two successive three-dimensional deformable models, whose evolutions are based on the level set framework. The first deformable model is driven by probability maps obtained from three MRI features: cortical thickness, relative intensity and gradient. These features correspond to the visual characteristics of FCD and allow discriminating lesions and normal tissues. In a second stage, the previous result is expanded towards the underlying and overlying cortical boundaries, throughout the whole cortical section. The method was quantitatively evaluated by comparison with manually traced labels in 18 patients with FCD. The automated segmentations achieved a strong agreement with the manuals labels, demonstrating the applicability of the method to assist the delineation of FCD lesions on MRI. This new approach may become a useful tool for the presurgical evaluation of patients with intractable epilepsy related to cortical dysplasia.

Adult↗
PubMed2006

Impaired proliferation and migration in human Miller-Dieker neural precursors.

OBJECTIVE: Miller-Dieker syndrome (MDS) is a malformation of cortical development that results in lissencephaly (meaning smooth brain). This disorder is caused by heterozygous deletions on chromosome 17p13.3, including the lissencephaly 1 (LIS1) gene. Various mouse models have been used as an experimental paradigm in understanding human lissencephaly, but clear limitations exist in these studies, particularly because mice are naturally lissencephalic. Thus, the objective of this article was to establish human neural precursor cell lines from postmortem MDS tissue and to characterize the pathological cellular processes that contribute to the human lissencephalic phenotype. METHODS: Human neural precursors were isolated and expanded from the frontal cortices of a 33-week postmortem fetus with MDS and an age-matched control subject. Relative rates of proliferation and cell death were assessed in vitro, whereas the migration of precursors was examined after transplantation in vivo. RESULTS: Precursors showed haploinsufficiency of the LIS1 gene and a reduction in LIS1 protein. Precursors could also differentiate into both neurons and glia. MDS precursors demonstrated impairments in neuronal migration, diminished rates of cell proliferation, and increased cell death. INTERPRETATION: These results suggest that, in addition to migration, disruption in cell proliferation could play a more important role in the development of lissencephaly than previously suspected.

1-Alkyl-2-acetylglycerophosphocholine Esterase↗
PubMed1975

The onset of synaptogenesis in rat temporal cortex.

The onset of synaptogenesis was studied in the temporal cortex of rat fetuses whose age ranged between 15 and 19 days of gestation. First synapses were found at a surprisingly early stage of cortical development: on day 16. These contacts showed relatively few vesicles and very inconspicuous membrane-thickenings. They were located in the marginal layer, above as well as below the narrow band formed by the newly arrived first neuroblasts of the prospective corticle plate. The postsynaptic structures were probably dendrites of the horizontally or obliquely orientated neurons scattered throughout the marginal layer (such neurons were seen even within the cell-dense band). On day 17, the cortical plate separated the differentiated cells definitely into a superficial and a deep population. As on the following days, synapses were found above and below the cortical plate but not within it. In addition to contacts showing the same features as those described on day 16, there were already synapses with numerous vesicles and clearly asymmetric membrane thickenings. On days 18 and 19 the borders of the cortical plate became more clear-cut. The well-differentiated neurons situated above and below this plate could now be identified as Retzius-Cajal cells of the prospective molecular layer and as polymorphous cells of the layer VI b respectively. The presence of axo-somatic contacts on these neurons provided direct evidence that both cell types are targets for synapses. Desmosome-like junctions were found even in the youngest fetuses studied. Their roughly symmetric membrane thickenings were clearly more conspicious than those of earliest synapses. Desmosome-like junctions occurred very frequently between structures which subsequently were never seen to become synaptically linked. During the entire period studied, numerous coated vesicles fused with cell membranes were noted. Such "open" vesicles were seen on neurons (sometimes in the immediate vicinity of synapses) but also on non-nervous, extracortical as well as intracortical structures. Thus there does not seem to be a specific relationship between desmosome-like junctions and coated vesicles on the one hand and synapse formation on the other.

Animals↗
PubMed2005

Distinct allelic variants of TSC1 and TSC2 in epilepsy-associated cortical malformations without balloon cells.

Epilepsy-associated malformations of cortical development (MCDs) comprise a variety of dysplastic and neoplastic lesions of yet undetermined molecular pathology. Histopathologic similarities between MCDs and dysplastic brain lesions in the autosomal inherited neurocutaneous phacomatosis tuberous sclerosis (TSC), which affects the TSC1 and/or TSC2 genes, suggest common pathogenetic mechanisms. Previous studies revealed different alterations of TSC1 and TSC2 in epilepsy-associated malformations and glio-neuronal tumors despite histopathologic similarities. In order to examine current clinico-pathologic classification systems of cortical malformations on the molecular level, we carried out a mutational analysis of TSC1 and TSC2 in a series of surgical specimens obtained from patients with FCD without Taylor type balloon cells (FCDIIa; n = 20), architectural dysplasias (FCDI; n = 15), nodular cortical heterotopias (NCH; n = 4), and heterotopic white matter neurons (WMNH; n = 19). In FCDIIa, abundant genomic polymorphisms were detected in TSC2 (intron 4) but no allelic variants observed in exon 17 of TSC1. This allelic distribution pattern is in contrast to findings in FCDI and WMNH but also to those previously reported in FCDIIb (Taylor's balloon cell type). The latter revealed increased frequencies of specific alleles only in TSC1. The determination of characteristic molecular genetic alterations in specific epilepsy-associated malformations will support a comprehensive clinico-pathologic classification system and help to identify molecular pathways with potential pathogenetic relevance. Our work is supported by DFG (SFB TR3 [AJB], DFG Bl 421/1-1 [IB]), BONFOR, and Deutsche Krebshilfe.

Alleles↗
PubMed1995

Recurrent excitation in neocortical circuits.

The majority of synapses in the mammalian cortex originate from cortical neurons. Indeed, the largest input to cortical cells comes from neighboring excitatory cells. However, most models of cortical development and processing do not reflect the anatomy and physiology of feedback excitation and are restricted to serial feedforward excitation. This report describes how populations of neurons in cat visual cortex can use excitatory feedback, characterized as an effective "network conductance", to amplify their feedforward input signals and demonstrates how neuronal discharge can be kept proportional to stimulus strength despite strong, recurrent connections that threaten to cause runaway excitation. These principles are incorporated into models of cortical direction and orientation selectivity that emphasize the basic design principles of cortical architectures.

Animals↗