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Neurogenetic gradients in the superior and inferior colliculi of the rhesus monkey.

The spatiotemporal patterns of neurogenesis in the superior colliculus (SC) and inferior colliculus (IC) were analyzed by plotting the positions of heavily labeled neurons in autoradiograms from a series of rhesus monkeys that had been exposed to 3H-thymidine at various embryonic (E) days and killed either shortly thereafter or at 2-3 months postnatally. Tectal neurons in this species are generated in the ventricular and subventricular zones surrounding the mesocoele (future Sylvian aqueduct) within the first third of the 165-day gestation period. Cells destined for the SC undergo final mitosis from E30 to E56, with peak proliferation from E38 to E43. These cells exhibit only a weak ventrodorsal gradient of neurogenesis and virtually no mediolateral or rostrocaudal gradients. Genesis of the neurons of the central nucleus (CN) of the IC also occurs between E30 and E56 and peaks around E43; but in contrast to cells of the SC, CN cells exhibit distinct rostrocaudal, lateromedial, and ventrodorsal gradients of genesis. Quantitative analysis revealed that whereas neurogenesis of the SC proceeds with about equal strength along the three cardinal axes, in the CN the lateral-medial gradient is significantly stronger than the anterior-posterior gradient. In addition, both the lateral-medial and ventral-dorsal IC gradients are significantly stronger than any SC gradients. Analysis of embryos sacrificed at short intervals following 3H-thymidine injection shows that the gradients are not caused by secondary lateral cell movement or by selective cell death. Thus, these findings suggest that within the generative zone of the midbrain tectum significant regional differences exist which result in distinctive spatiotemporal patterns of proliferation for the neurons of the primate superior and inferior colliculi.

Animals↗

The hippocampal mossy fiber system of the rat studied with retrograde tracing techniques. Correlation between topographic organization and neurogenetic gradients.

The topographical organization of the hippocampal mossy fiber system, which connects the dentate granule cells with the pyramidal cells of the regio inferior, has been examined in rats with retrograde tracing methods. Following the application of the fluorescent dye True Blue to different parts of the mossy fiber layer in the hippocampal regio inferior, retrogradely labeled granule cells were observed in the dentate fascia. The distribution of the labeled cells within the dentate granule cell layer indicates that all mossy fibers have an almost parallel, slightly descending course in regio inferior near the dentate hilus. In the ventricular part of region inferior, particularly toward the transition to the regio superior, the mossy fibers are sorted out according to the position of their parent cell bodies within the granular layer. Near the transition to regio superior the fibers from lateral granule cells extend both septally and temporally over a longer distance than the fibers from more medial cells. Similarly, the fibers coming from the superficial cells extend both septally and temporally over a longer distance than those from the deep cells. The mossy fibers arising from a specific septotemporal level of the dentate fascia innervate a segment of the regio inferior that extends approximately 180 micrometer above to approximately 1,600 micrometer below the level of origin. Similar results were obtained following injections of Nuclear Yellow and horseradish peroxidase. Since previous studies have demonstrated that the granule cells are formed along gradients from lateral to medial and from superficial to deep, there appears to be a correlation between the formation, and hence the position, of the granule cells and the topography of their projection into the regio inferior.

Animals↗

An integrated, functionally annotated gene map of the DXS8026-ELK1 interval on human Xp11.3-Xp11.23: potential hotspot for neurogenetic disorders.

Human chromosome Xp11.3-Xp11.23 encompasses the map location for a growing number of diseases with a genetic basis or genetic component. These include several eye disorders, syndromic and nonsyndromic forms of X-linked mental retardation (XLMR), X-linked neuromuscular diseases and susceptibility loci for schizophrenia, type 1 diabetes, and Graves' disease. We have constructed an approximately 2.7-Mb high-resolution physical map extending from DXS8026 to ELK1, corresponding to a genetic distance of approximately 5.5 cM. A combination of chromosome walking and sequence-tagged site (STS)-content mapping resulted in an integrated framework and transcript map, precisely positioning 10 polymorphic microsatellites (one of which is novel), 16 ESTs, and 12 known genes (RP2, PCTK1, UHX1, UBE1, RBM10, ZNF157, SYN1, ARAF1, TIMP1, PFC, ELK1, UXT). The composite map is currently anchored with 89 STSs to give an average resolution of approximately 1 STS every 30 kb. By a combination of EST database searches and in silico detection of UniGene clusters within genomic sequence generated from this template map, we have mapped several novel genes within this interval: a Na+/H+ exchanger (SLC9A7), at least two zincfinger transcription factors (KIAA0215 and Hs.68318), carbohydrate sulfotransferase-7 (CHST7), regucalcin (RGN), inactivation-escape-1 (INE1), the human ortholog of mouse neuronal protein 15.6, and four putative novel genes. Further genomic analysis enabled annotation of the sequence interval with 20 predicted pseudogenes and 21 UniGene clusters of unknown function. The combined PAC/BAC transcript map and YAC scaffold presented here clarifies previously conflicting data for markers and genes within the Xp11.3-Xp11.23 interval and provides a powerful integrated resource for functional characterization of this clonally unstable, yet gene-rich and clinically significant region of proximal Xp.

Chromosome Mapping↗

Clinical and molecular neurogenetics in neurosurgery.

This chapter describes the basic principles of molecular genetics, particularly in relation to gene mapping and isolation (positional cloning). The application of this technology is illustrated by progress in elucidating the molecular basis of inherited tumour syndromes, including neurofibromatosis types 1 and 2 and von Hippel-Lindau disease, and molecular studies of tumourigenesis in malignant gliomas.

Brain Neoplasms↗

Abnormalities of cerebellar foliation and fissuration: classification, neurogenetics and clinicoradiological correlations.

Several genes have been found to influence the different cells involved in the processes of foliation and fissuration in the mouse and rat cerebellum. In the light of these new concepts and on the basis of the imaging findings in 42 patients, a classification is proposed for abnormalities of foliation and fissuration. On the basis of recent genetic and experimental evidence on mechanisms which control the origin of the cerebellum, it is suggested that abnormalities of foliation and fissuration form a single group, with a spectrum of severity. Some patients have only abnormal fissuration of the anterior lobe (type 1a) and others additional dysplasia of the anterior and part of the posterior lobe (type 1b). Extension of abnormalities into the hemispheres is often seen in the latter group. A second group has vermian and hemisphere abnormalities (type 2). In addition to the malformation of the anterior lobe of the vermis, three different hemispheric lesions can be seen in this group: cortical dysgenesis, hypertrophy of the cerebellar cortex, and malorientation of the folia. The mild abnormalities (type 1a) can be considered an incidental observation without clinical relevance. The moderate and severe cerebellar anomalies (type 1b and 2) are always associated with cerebellar symptoms and/or signs.

Animals↗

Neurogenetical segregation of the vestibulospinal neurons in the rat.

The time of origin of the vestibulospinal projection neurons was determined by a double-labeling method using 5-bromodeoxyuridine (BrdU), the thymidine analogue, and Fluoro-Gold (FG), a retrograde fluorescent tracer. Rat fetuses were exposed to BrdU in utero to label the vestibular neurons on one of the embryonic (E) days between E12 and E15. Upon reaching adulthood, the rats were given unilateral injections of FG into the cervical cord to identify the spinal projection neurons. Brainstem sections were immunohistochemically processed for BrdU and then examined for neurons that were both BrdU-positive and FG-positive in the vestibular nuclei. In the lateral vestibular nucleus (LVe), most of the vestibulospinal neurons were generated on E12. In the inferior vestibular nucleus (IVe), the vestibulospinal neurons were produced almost equally on both E12 and E13. In the medial vestibular nucleus (MVe), the vestibulospinal neurons were generated consistently on days between E12 and E14 with a mild peak on E13. The present results thus demonstrate that genesis of the vestibulospinal neurons occurs sequentially in the following order: firstly in the LVe, secondly in the IVe, and finally in the MVe. The different sequential generation of vestibulospinal neurons among the LVe, MVe and IVe may reflect the fact that the vestibulospinal projections are differentially organized depending on the nature of each subnucleus.

Animals↗

Neurogenetic mechanisms of learning: a phylogenetic perspective.

Common psychiatric disorders often involve abnormal patterns of adaptive response to environmental stimuli. Thus, an understanding of the pathophysiology and inheritance of such maladaptation requires specification of the underlying neural mechanisms involved in learning, which is broadly defined as the modification of behavior as a result of individual experience. The phylogenetic development of learning ability in animals is shown to proceed by a sequence of discrete steps in which non-associative learning is augmented successively by classical conditioning to aversive stimuli, followed by classical conditioning to food and other rewarding stimuli, then exploratory learning about novel habitats and operant conditioning of behavioral responses, and finally conceptual learning ability. As a result of this complex phylogenetic history, adaptive responses to the environment in mammals including human beings is multidimensional. A model of the structure of stimulus-response and cognitive-processing characteristics in human beings is described. The model is discussed in terms of its evolutionary advantages for survival and reproductive fitness as well as its importance in understanding susceptibility to psychiatric disorders, including personality and anxiety disorders.

Animals↗

A neurogenetic and morphogenetic approach to hippocampal functions based on individual differences and neurobehavioral covariations.

To investigate the neural substrate of information processing, the within group inter-individual behavioral differences were related to the fine variations in some components of the architecture of the intact hippocampus by multivariate analyses of variance and correlative analyses. For, the extent of the intra/infrapyramidal mossy fibers, covering the hippocampal CA3-regio inferior (IIP-MF, revealed by Timm-staining), and the individual high-affinity maximal glucocorticoid receptor binding (HCB, measured by in vitro cytosol preparations with [3H]corticosterone as ligand), were assessed in adult male albino rats of the Naples High-Excitability (NHE) and Naples Low-Excitability (NLE) psychogenetically selected lines, and of a Sprague-Dawley random-bred stock (NRB) as unselected controls. The IIP-MF and the HCB were assumed as hippocampal hardware and software traits, respectively, and entered in a matrix with activity and defecation scores in a Làt-maze as behavioral covariates. Two dimensions were identified by discriminant function analyses tentatively labelled as "spatial" and "non-spatial" by the nature of the variables contributing with a high loading to the dimension. The IIP-MF and HCB contributed mostly to spatial processes and to a lower extent to emotional processes. The neuro-behavioral covariations of IIP-MF with arousal (A) and long-term habituation (LTH), computed by correlative analyses on the overall population (all rats combined), turned out to be of inverted-U type (quadratic function), i.e. positive in NLE, negative in NHE with no correlation in NRB. For HCB receptors, the covariations were quadratic with A, and of the S-type (cubic function), i.e. positive in NLE, negative in NRB and positive in NHE with LTH. Since these rat lines are located along a "continuum" with NLE < RB < NHE, they are assumed to represent entirely this subpopulation. For, the non-linear neuro-behavioral relationships might reveal (i) constraints on the expression of arousal and habituation to novelty; and (ii) that the hippocampus appears to be one such device exerting a modulatory role in the processing of "spatial" and "non-spatial" behavioral components.

Adrenal Cortex↗

The inv dup(15) or idic(15) syndrome: a clinically recognisable neurogenetic disorder.

The chromosome region 15q11q13 is known for its instability, and many rearrangements may occur in this imprinted segment: deletions associated either with Angelman syndrome (AS) or with Prader-Willi syndrome (PWS), according to parental origin; translocations; inversions; and supernumerary marker chromosomes formed by the inverted duplication of proximal chromosome 15. Inv dup(15) constitute the most common of the heterogeneous group of the extra structurally abnormal chromosomes, and their presence results in tetrasomy 15p and partial tetrasomy 15q. Inv dup(15), containing the Prader-Willi/Angelman syndrome region, are associated with altered behaviour, developmental delay/mental retardation, and seizures/epilepsy. Clinicians should suspect this syndrome in any infant/child with early central hypotonia, minor dysmorphic features, developmental delay, autism or autistic-like behaviour, and who subsequently develops hard to control seizures/epilepsy. Diagnosis is confirmed by standard cytogenetic techniques and FISH analysis. Although, about 100 cases have been reported to date, limited data are available on the natural history. To obtain better information on diagnosis and outcome in a clinical setting, we reviewed the available literature on clinical and behavioural phenotype of inv dup(15) syndrome.

Abnormalities, Multiple↗