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PubMed1982

The effect of neonatal 6-hydroxydopamine treatment on synaptogenesis in the visual cortex of the rat.

It has been proposed repeatedly that the noradrenergic (NE) system may exert an influence on cortical development. We have tested this proposition by examining synaptogenesis in the visual cortex of rats whose NE afferents were selectively lesioned by injections of the neurotoxin 6-hydroxydopamine (6-OHDA). Control littermates were injected with equal volumes of vehicle. Montages of electron micrographs covering approximately 50 micrometers-wide strips of cortex were assembled from both groups of animals at 2,4,6,8,14, and 90 days of age. Synapse counts revealed a significantly higher density of synapses in the cortex of 6-OHDA-treated rats during the first week of postnatal life. The difference between the experimental and control rats was less apparent during the second postnatal week, and at day 90 the densities of synapses were similar for the two groups of animals. The enhanced density, which was the result of the increased number of Gray's type I synapses, was confined to the subplate region at day 2 but became more widespread in the cortex at subsequent stages of development. From these observations it would appear that the NE system exerts an inhibitory influence on synapse formation in the visual cortex in early postnatal life.

Age Factors↗
PubMed1989

Connectional analysis of the ipsilateral and contralateral afferent neurons of the superior temporal region in the rhesus monkey.

The interhemispheric and ipsilateral afferents of the superior temporal region (STR) were investigated with the aid of fluorescent retrograde tracers (Diamidino Yellow and Fast Blue). Different tracers were injected in selected cortical areas of the STR of each hemisphere of four rhesus monkeys. The results show that the interhemispheric afferents originate not only from the homotopic but also from heterotopic areas. The heterotopic areas giving rise to interhemispheric projections correspond to cortical areas of the origin of the ipsilateral projections. Although there is considerable overlap of labeled neurons of both afferent systems, only occasional double-labeled neurons are found. Whereas the laminar patterns of ipsilateral neurons of origin vary considerably, the interhemispheric projection neurons are located mainly in cortical layer III. This study provides additional information about the ipsilateral connectional organization of the superior temporal region. That is, the primary auditory area receives projections not only from adjacent lateral and medial cortical regions but also from adjoining rostral and caudal cortical regions. Thus, the highly differentiated primary auditory cortical area receives strong projections from the surrounding less-differentiated cortical regions. This connectional pattern is discussed from the perspective of the growth ring concept of cortical development.

Animals↗
PubMed1990

Developmental history of the transient subplate zone in the visual and somatosensory cortex of the macaque monkey and human brain.

The cytological organization and the timetable of emergence and dissolution of the transient subplate zone subjacent to the developing visual and somatosensory cortex were studied in a series of human and monkey fetal brains. Cerebral walls processed with Nissl, Golgi, electron-microscopic, and histochemical methods show that this zone consists of migratory and postmigratory neurons, growth cones, loosely arranged axons, dendrites, synapses, and glial cells. In both species the subplate zone becomes visible at the beginning of the mid-third of gestation as a cell-poor/fiber-rich layer situated between the intermediate zone and the developing cortical plate. The subplate zone appears earlier in the somatosensory than in the visual area and reaches maximal width at the beginning of the last third of gestation in both regions. At the peak of its size the ratio between the width of the subplate zone and cortical plate in the somatosensory cortex is 2:1 in monkey and 4:1 in man while in the occipital lobe these structures have about equal width in both species. The dissolution of the subplate zone begins during the last third of gestation with degeneration of some subplate neurons and the relocation of fiber terminals into the cortex. The subplate zone disappears faster in the visual than in the somatosensory area. The present results together with our previous findings support the hypothesis that the subplate zone may serve as a "waiting" compartment for transient cellular interactions and a substrate for competition, segregation, and growth of afferents originated sequentially from the brain stem, basal forebrain, thalamus, and from the ipsi- and contralateral cerebral hemisphere. After a variable and partially overlapping time period, these fibers enter the cortical plate while the subplate zone disappears leaving only a vestige of cells scattered throughout the subcortical white matter. A comparison between species indicates that the size and duration of the subplate zone increases during mammalian evolution and culminates in human fetuses concomitantly with an enlargement of cortico-cortical fiber systems. The regional difference in the size, pattern, and resolution of the subplate zone correlates also with the pattern of cerebral convolutions. Our findings indicate that, contrary to prevailing notions, the subplate may not be a vestige of the phylogenetically old network but a transient embryonic structure that expanded during evolution to subserve the increasing number of its connections.

Animals↗
PubMed1992

Distribution of corticotropin-releasing factor-like immunoreactivity in squirrel monkey (Saimiri sciureus) amygdala.

Previous anatomical studies of corticotropin-releasing factor (CRF)-like immunoreactivity in rat brain have reported prominent clustering of neuronal elements containing this peptide within the amygdala. The highest concentrations of both CRF-positive cells and fibers were evident in the central nucleus, an observation consistent with the putative role of this peptide in autonomic and endocrine regulation. In addition, lower densities of CRF-positive somata and processes have been noted in other amygdaloid nuclei. However, the distribution of CRF-like immunoreactivity in the amygdala has not been described for any primate species. Such a description would be of interest since substantial differences in the distribution of CRF in rodent and primate have been reported for other brain regions. The present study uses immunohistochemical methods, with a polyclonal antiserum directed against the human form of CRF, to determine the distribution of this peptide in non-colchicine-treated monkeys (Saimiri sciureus). Within the amygdaloid complex, the most numerous and concentrated collections of CRF-positive neurons were seen in the basal and lateral nuclei. The highest densities of CRF-positive fibers and terminals were seen in the lateral and central amygdaloid nuclei. Moderately dense plexuses of CRF-positive fibers also were seen in layer Ia of the periamygdaloid cortex, nucleus of the lateral olfactory tract, anterior and posterior cortical nuclei, and the medial nucleus. Thus, the distribution of CRF-like immunoreactivity differs substantially in monkey and rat amygdala. Since CRF-positive perikarya in monkey are most prominent in nuclei with pronounced interconnections with neocortex, these differences may be an integral component of the increased cortical development that characterizes the primate brain.

Amygdala↗
PubMed1995

Early postmitotic neurons transiently express TOAD-64, a neural specific protein.

To identify proteins involved in the early development of the mammalian cerebral cortex, we previously used two-dimensional gels to compare proteins synthesized at different stages in corticogenesis in the embryonic rat at embryonic day 14 (E14), E17, and E21. During this period, the cortex develops from a morphologically homogeneous population of proliferative precursor cells into a complex structure containing a diverse array of terminally differentiated neurons. Several proteins are up-regulated coincident with the generation of postmitotic neurons. Here we describe the purification, partial amino acid sequencing, and characterization of one of these proteins, TOAD-64 (Turned On After Division; 64 kDa), using polyclonal antisera to two synthetic peptides from the protein. This analysis reveals that TOAD-64 is a 64,000 Da protein that increases in abundance over the period of corticogenesis and then subsequently decreases to very low levels in the adult. The protein is neural specific and is expressed by postmitotic neurons as they begin their migration out of the ventricular zone into the developing cortical plate. It is expressed in advance of most other neuronal proteins. Progenitor cells do not express TOAD-64. Therefore, this protein is a marker for postmitotic cells that have made a commitment to a neuronal phenotype. The extremely early expression, the relative abundance in newly born neurons, as well as the restriction in expression to the period of initial neuronal differentiation suggest that TOAD-64 may be a key structural protein for early neuronal function.

Amino Acid Sequence↗
PubMed1984

Chronic toxicity of S-(trans-1,2-dichlorovinyl)-L-cysteine in mice.

S-(trans-1,2-Dichlorovinyl)-L-cysteine (DCVC) exposure causes acute renal tubular cytotoxicity. To further characterize the effects of DCVC, a chronic study was undertaken. Male Swiss-Webster mice received DCVC dissolved in their drinking water at 0.01, 0.05 and 0.1 mg ml-1. At 4, 8, 21 and 37 weeks, animals were terminated. Bladders, spleens, livers, kidneys and eyes were removed for histopathological examination. At 0.05 and 0.1 mg ml-1 DCVC, growth retardation was evident by 21 weeks. By 26 weeks, all animals in the 0.1 mg ml-1 group had developed cortical cataracts. Cytomegaly, nuclear hyperchromatism and multiple nucleoli were noted in the cells of the pars recta region of the kidney by 4 weeks and correlated to time and dose. At later time points, renal tubular atrophy and early interstitial fibrosis were evident. The epithelial cytological cellular abnormalities appear to be dose-related. Minor pathological changes were noted in the spleen, while there was no effect on the liver or bladder. Chronic ingestion of DCVC results in severe kidney injury.

Animals↗
PubMed2004

Differential expression of Pax6 and Ngn2 between pair-generated cortical neurons.

Progenitor cells that generate neuron pairs ("pair progenitor cells") are implicated in mammalian cortical development, and their division has been thought to be "symmetric." However, asymmetric growth of two sister neurons generated by the division of a pair progenitor cell would lead to more efficient generation of neuronal diversity in the cortex. To explore mechanisms by which pair progenitor cells provide neuronal diversity, we examined molecular differences between a pair of neurons generated in clonal-density culture. Time-course analysis for the acquisition of neuronal markers and the disappearance of Pax6 and Neurogenin2 (Ngn2) demonstrated that 1) these transcription factors are expressed transiently in some but not all young neurons and 2) some neuron pairs showed uneven/asymmetric expression of Pax6 (19.5%) or Ngn2 (23.8%), whereas other pairs were either symmetrically positive or negative. Asymmetric Pax6 distribution in neuron pairs was not associated with asymmetric distribution of Numb, which raises an intriguing possibility, that Pax6 asymmetry in neuron pairs is produced by an alternative mode of the cell autonomous mechanisms. Stage-dependent changes were noted in the pattern of Ngn2 retention in daughter neurons, reflecting qualitative changes in the pair progenitor population. We suggest that pair progenitor cells contribute to the generation of neuronal diversity through cell-intrinsic heterogeneity and asymmetric division.

Animals↗
PubMed2005

Frontal bilateral megalencephaly: fetal and autopsy MR evaluation of an unclassified malformation.

OBJECTIVE: To describe an unreported brain malformation with in utero onset. METHODS: A 21-weeks-of-gestational-age fetus underwent prenatal MR imaging because of macrocephaly detected by ultrasound. Prenatal MR imaging revealed a complex brain malformation. At 22 weeks of GA, pregnancy was terminated; an MR autopsy study was also performed. RESULTS: MR imaging revealed frontal bilateral megalencephaly and malformation of cortical development, suggesting polymicrogyria. These findings do not fit into any of the known megalencephalic syndromes. CONCLUSIONS: To our knowledge, this is a previously unreported malformation. Fetal and autoptic MR examination have been the best tools in understanding this complex brain pathology, allowing a more complete genetic counseling.

Adult↗
PubMedDate not supplied

Diagnosis of congenital CMV infection via dried blood spots.

Cytomegalovirus (CMV) infection is the most frequent congenital infection in humans and can cause permanent damage--particularly neurological--in about 20% of those infected, with or without symptoms at birth. Laboratory diagnosis is essential on account of the relatively non-specific clinical manifestations in symptomatic newborns but also because of the high frequency of asymptomatic cases that are nevertheless at risk of lesions later in life. However, these tests need samples taken within 3 weeks of birth to distinguish congenital infection from the more common, but clinically benign, perinatal infection. Tests for viral DNA have proved a valid means of diagnosing congenital CMV infection in neonatal blood dried on paper (DBS) widely used in screening for metabolic and genetic diseases, as an alternative to the conventional urine culture method. The DBS test is simpler, faster and less costly than viral isolation; in addition the samples can be safely stored for long periods, so diagnosis can be made even after several years. The sensitivity and specificity of the DBS test, compared to the reference method, have been reported to range between 71 and 100% and 99 and 100%, respectively, depending on the different studies and diagnostic criteria applied. The most interesting applications reported so far involve retrospective determination of the impact of congenital CMV in sensorineural deafness, abnormalities of cortical development, neonatal cholestasis and surveys of the prevalence of this infection in various populations. The test might be useful in the future for neonatal screening with a view to treating neonates and so avoiding the damage this disease can cause.

Cytomegalovirus↗
PubMed2002

Temporal Lobe Resections in Children with Epilepsy: Neuropsychiatric Status in Relation to Neuropathology and Seizure Outcome.

The purpose of this work was to relate clinical neuropsychiatric findings to histopathological diagnoses and seizure outcome in a retrospective study of 16 children undergoing temporal lobe resections due to medically intractable epilepsy. These children constitute a heterogeneous group in which neuropsychiatric symptoms were common. The results of this study indicate a correlation between malformations of cortical development, less chance of seizure freedom, and neuropsychiatric problems in children with pharmacoresistant temporal lobe epilepsy. It is important to include neuropsychiatric assessments pre- and postoperatively and to inform parents that symptoms of autism spectrum disorders may or may not be improved after epilepsy surgery.

Journal Article↗
PubMed1993

Cellular organization in rat somatosensory cortex: effects of sex and laterality.

Layer IV of rodent somatosensory cortex contains distinct arrangements of cells characterized as barrels. When barrels first form in rats, each barrel consists of a cell-dense "wall" and a cell-sparse "hollow." With age, the distinction of the boundary between barrel walls and hollows diminishes. Cellular arrangements within barrels were quantified to test whether the barrels are influenced by sex and laterality during cortical development. A computer-assisted method was developed to measure cell densities in relation to barrel boundaries. The boundaries between barrel walls and hollows were determined in tissue double-stained for Nissl substance and cytochrome oxidase histochemistry. The distinction between barrel walls and hollows revealed by Nissl stains differed significantly between anterior and posterior barrels. This distinction declined significantly in anterior barrels from Postnatal Day 10 (P10) to P30. The area of cortex containing barrels was estimated from composites of Nissl-stained sections. At P20 the detectable barrel cortex area was larger on the right in females and on the left in males resulting in a significant sex difference in barrel cortex asymmetry. This sex difference in barrel cortex laterality was detected only in Nissl-stained tissue; there were no differences attributable to sex or side in barrel cortex area analyzed for cytochrome oxidase reactivity. We hypothesize that sex-dependent differences in barrel cortex structure result from lateralized differences in cellular organization.

Animals↗
PubMed1999

Mature astrocytes transform into transitional radial glia within adult mouse neocortex that supports directed migration of transplanted immature neurons.

Neuronal migration is an essential step in normal mammalian neocortical development, and the expression of defined cellular and molecular signals within the developing cortical microenvironment is likely crucial to this process. Therapy via transplanted or manipulated endogenous precursors for diseases which involve neuronal loss may depend critically on whether newly incorporated cells can actively migrate to repopulate areas of neuronal loss within the adult brain. Previous studies demonstrated that embryonic neurons and multipotent precursors transplanted into the neocortex of adult mice undergoing targeted apoptosis of pyramidal neurons migrate long distances into neuron-deficient regions, undergo directed differentiation, accept afferent synaptic input, and make appropriate long-distance projections. The experiments presented here: (1) use time-lapse digital confocal imaging of neuronal migration in living slice cultures to assess cellular mechanisms utilized by immature neurons during such long distance migration, and (2) identify changes within the host cortical astroglial population that may contribute to this migration. Prelabeled embryonic day 17 mouse neocortical neurons were transplanted into adult mouse primary somatosensory cortex undergoing targeted apoptotic degeneration of callosal projection neurons. Four to 7 days following transplantation, living slice cultures containing the region of transplanted cells were prepared and observed. Sequential time-lapse images were recorded using a video-based digital confocal microscope. Transplanted cells displayed bipolar morphologies characteristic of migrating neuroblasts and moved in a saltatory manner with mean rates of up to 14 microm/h. To investigate whether a permissive glial phenotype may provide a potential substrate for this directed form of neuronal migration, slice cultures were immunostained with the RC2 monoclonal antibody, which identifies radial glia that act as a substrate for neuronal migration during corticogenesis. RC2 does not label mature stellate astrocytes, which express glial fibrillary acidic protein (GFAP). RC2 expression was observed in glial cells closely apposed to migrating donor neurons within the slice cultures. The timing and specificity of RC2 expression was examined immunocytochemically at various times following transplantation. RC2 immunostaining within regions of neuronal degeneration was transient, with peak staining between 3 and 7 days following transplantation. Strongly RC2-immunoreactive cells that did not express GFAP were found within these regions, but not in distant cortical regions or within control brains. RC2-positive cells were identified in recipient transgenic mice which express beta-galactosidase under a glial specific promoter. Coexpression of RC2 and beta-galactosidase identified these cells as host astroglia. These results demonstrate that adult cortical astrocytes retain the capacity to reexpress an earlier developmental phenotype that may partially underlie the observed active migration of transplanted neurons and neural precursors. Further understanding of these processes could allow directed migration of transplanted or endogenous precursors toward therapeutic cellular repopulation and complex circuit reconstruction in neocortex and other CNS regions.

Animals↗
PubMed2002

Tsc2 null murine neuroepithelial cells are a model for human tuber giant cells, and show activation of an mTOR pathway.

Cortical tubers are developmental brain malformations in the tuberous sclerosis complex (TSC) that cause epilepsy and autism in TSC patients whose pathogenesis is uncertain. Tsc2 null murine neuroepithelial progenitor (NEP) cells display persistent growth when growth factors are withdrawn, express GFAP at high levels, and have reduced expression of a set of early neuronal lineage markers. Tsc2 null NEP cells exhibit aberrant differentiation into giant cells that express both beta III-tubulin and GFAP and that are morphologically similar to giant cells in human tubers. Tsc2 null giant cells and tuber giant cells have similar transcriptional profiles. Tsc2 null NEP cells express high levels of phosphorylated S6kinase, S6, Stat3, and 4E-BP-1, which is reversed by treatment with rapamycin, an inhibitor of mTOR. We conclude that giant cells in human tubers likely result from a complete loss of TSC2 expression and activation of an mTOR pathway during cortical development.

Adaptor Proteins, Signal Transducing↗
PubMed2002

Neurodevelopmental aspects of spatial navigation: a virtual reality fMRI study.

Navigation in spatial contexts has been studied in diverse species, yielding insights into underlying neural mechanisms and their phylogenetic progression. Spatial navigation in humans is marked by age-related changes that may carry important implications for understanding cortical development. The emergence of "allocentric" processing, reflecting that ability to use viewer-independent spatial abstractions, represents an important developmental change. We used fMRI to map brain regions engaged during memory-guided navigation in a virtual reality environment in adolescents and adults. Blood oxygen level-dependent (BOLD) signal was monitored in eight adolescents and eight adults in a 1.5-T MRI scanner during three conditions: (1) memory-guided navigation (NAV); (2) arrow-guided navigation (ARROW); and (3) fixation (FIX). We quantified navigation ability during scanning and allocentric memory after scanning, based on subjects' ability to label a previously unseen, aerial view of the town. Adolescents and adults exhibited similar memory-guided navigation ability, but adults exhibited superior allocentric memory ability. Memory-guided navigation ability during scanning correlated with BOLD change between NAV/ARROWS in various regions, including a right frontal and right-anterior medial temporal lobe region. Age group and allocentric memory together explained significant variance in BOLD change in temporoparietal association cortex and the cerebellum, particularly in the left hemisphere. Consistent with developmental models, these findings relate maturation in the coding of spatial information to functional changes in a distributed, left-lateralized neural network.

Adolescent↗
PubMed1988

Do muscle afferents contribute to the cervical response evoked by electrical stimulation of the median nerve in man?

The possible contribution of low threshold muscle afferents to the postsynaptic component (N13) of the cervical response evoked by electrical stimulation of the median nerve (MN) was investigated in normal subjects. Electroneurographic (ENG) and electromyographic (EMG) correlates of the reflex motoneuronal discharge (RMND) were recorded simultaneously. A. No reflex activity could be elicited by stimulation of the MN at the wrist, at least in the resting subjects, while well developed ENG (P2 efferent volley) and EMG (H reflex) monosynaptic responses occurred following stimulation of the MN at the elbow at suitable strengths. In neither case could a surface correlate of interneuronal activity evoked by muscle afferents be demonstrated. B. Recruitment curves showed that at stimulus intensities above maximal for the H reflex both P2 and H responses started to decrease until they completely disappeared, while N13 showed further enhancement. C. Subthreshold conditioning stimulation of the MN enhanced both P2 and H responses, while vibratory muscle stimuli provoked a clearcut suppression of these two responses. In contrast, N13 was completely unaffected by either manoeuvre. D. No cervical evoked activity could be detected following tendon tapping of the anterior forearm muscles in spite of the appearance of well developed cortical responses and the ENG and EMG correlates of the T reflex. E. Conditioning volleys elicited by tendon taps of the anterior forearm muscles suppressed both P2 and H responses following stimulation of the MN at the elbow without affecting the related N13 component. Conditioning supramaximal stimulation of the MN at the wrist suppressed the N13 component of the cervical response evoked by stimulation of the MN at the elbow without affecting the related reflex responses. No component chronologically related to the RMND could be recorded at the posterior neck region during suppression of N13, thus ruling out the possibility that failure to detect the RMND (as well as its interneuronal concomitants) with cervical electrodes is due to a masking effect of the N13 component. G. Conditioning tendon taps of anterior forearm muscles provoked a clearcut reduction of the primary cortical response to finger stimulation without affecting the postsynaptic component of the related cervical response. It is concluded that neither segmental (motoneuronal or interneuronal in origin) nor ascending postsynaptic impulses generated in the spinal cord by stimulation of low threshold muscle afferents contribute to N13, the latter being probably due to activation of both short and long axoned spinal neurons by cutaneous afferents.

Adult↗
PubMed1982

Pathogenesis of four-layered microgyric cortex in man.

Microgyria (polygria, polymicrogyria) has stimulated continued interest since its first description by Meschede [28]. Based on analysis of case material, available staining techniques, and known principles of human cortical development, subsequent investigators have proposed numerous theories to explain its pathogenesis. We have studied a case which cannot be fully explained by these previously proposed theories. In this case, four-layered microgyria is present bilaterally in middle cerebral artery distribution, but in one hemisphere, in the center of the malformed area, the deep acellular and cellular layers are replaced by radially aligned neurons extending ectopically into prospective white matter. Analysis of the findings in this case provide evidence that the recently described pathogenetic mechanism observed in a rat model of this malformation [15,16] is applicable to its formation in man.

Animals↗
PubMed1992

Glutamate decarboxylase in developing rat neocortex: does it correlate with the differentiation of GABAergic neurons and synapses?

Postnatal development of glutamate decarboxylase was studied in the rat cerebral cortex. Two methods were used: estimation of the enzymatic activity of glutamate decarboxylase in homogenates of developing cortical tissue and visualization of structures containing glutamate decarboxylase-like immunoreactivity. Glutamate decarboxylase-like immunoreactivity appeared first in perikarya and dendrites and only later in axons and axon varicosities. The most rapid increase in the glutamate decarboxylase activity took place during the second postnatal week and this coincided with a rapid increase in the density of axon varicosities containing glutamate decarboxylase-like immunoreactivity but preceded the most rapid phase in the formation of GABAergic synapses by several days. However, there was a change in the characteristics of glutamate decarboxylase which correlated with GABA synaptogenesis: two fractions of glutamate decarboxylase with different sensitivities to the activating effects of Triton X-100 could be distinguished as from about the time when most of the GABAergic synapses are formed.

Animals↗
PubMedDate not supplied

Neurophysiological mechanisms of the attention disturbance in children with learning difficulties.

The features of orientation reaction (OR) and the background EEG were investigated with the purpose of studying the neurophysiological mechanisms of the disturbance of voluntary attention in children aged 6.5-9 years with learning difficulties caused by delayed mental development (DMD). A decrease in the expressivity of components of the OR as compared with the norm, discovered in a situation of involuntary attention against a background of insufficiently developed cortical rhythmicity in the alpha range, was compensated for given an increase in the significance of the stimuli. These facts support the hypothesis of a deficit in regulatory corticofugal influences in children with DMD. The inadequacy of the engagement of central regions of the cortex characteristic of children with DMD in the realization of OR in a situation of directed attention can be regarded as a reflection of disturbances of the integrative activity of the brain.

Attention↗