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PubMed1993

[The supplemental motor area].

Following an introduction dealing with the developments which led to the discovery of the supplementary motor area (SMA), its anatomy and neuronal connections are described. Subsequently, a report concerning the pathology of the SMA (epilepsy, tumours, ablations, defects and possible neuroleptic effects) and related experimental findings is presented. This is followed by a description of the motor function, and especially the speech motor function of the SMA. The article concludes with an exposition of Sir John C. Eccles' interpretation of the SMA as providing the basis for a naive solution of the mind-body dualism.

Animals↗
PubMed1998

The pachygyria-polymicrogyria spectrum of cortical dysplasia in X-linked hydrocephalus.

Neural cell adhesion molecules (CAM) play important roles in neural development, neurite outgrowth, axonal guidance, fasciculation and synapse formation. Neuropathological studies of X-linked hydrocephalus (XLH) associated with L1 CAM mutations emphasize marked hypoplasia of the pyramidal tract, agenesis of the corpus callosum and septum pellucidum, and a thin cerebral mantle with hypoplastic white matter, but there are no detailed studies of the cerebral cortex in the literature. We report clinical, neuroimaging, and neuropathological findings in three boys with XLH. All had severe congenital hydrocephalus with marked thinning of the cerebral mantle and severe development disabilities. The brain specimens from the three boys showed both pachygyria and polymicrogyria, hypoplasia of the medullary pyramids, hypoplasia of the corpus callosum, small anterior commissure, hypoplasia and poorly differentiated hippocampi. A small but patent aqueduct was present in all three brains. Despite the extensive cerebral malformations, the cortex in all three brains showed normal-appearing laminar cortical neuronal architecture and absence of gliosis. In XLH, it is likely that the poor developmental outcome of spasticity, contractures and severe mental retardation results from a disturbance of neuronal connectivity, fasciculation, and synapse formation rather than aqueductal stenosis, increased intracranial pressure, or abnormal neuroblast migration.

Antigens, Surface↗
PubMed2006

Dictyostelium myosin II mechanochemistry promotes active behavior of the cortex on long time scales.

Cell cortices rearrange dynamically to complete cytokinesis, crawlin response to chemoattractant, build tissues, and make neuronal connections. Highly enriched in the cell cortex, actin, myosin II, and actin crosslinkers facilitate cortical movements. Because cortical behavior is the consequence of nanoscale biochemical events, it is essential to probe the cortex at this level. Here, we use high-resolution laser-based particle tracking to examine how myosin II mechanochemistry and dynacortin-mediated actin crosslinking control cortex dynamics in Dictyostelium. Consistent with its low duty ratio, myosin II does not directly drive active bead motility. Instead, myosin II and dynacortin antagonistically regulate other active processes in the living cortex.

Animals↗
PubMed1983

Functional role for vasoactive intestinal polypeptide in the caudate nucleus: a 2-deoxy[14C]glucose investigation.

The quantitative autoradiographic 2-deoxy-[14C]glucose technique has been used with conscious rats to investigate the functional consequences (reflected as alterations in local rates of glucose utilization) of unilateral intrastriatal administration of vasoactive intestinal polypeptide. Intrastriatal administration of vasoactive intestinal polypeptide (20 pmol) significantly increased local glucose utilization in the injected striatum, where the increased use was localized in small punctate areas (100-500 microns wide in coronal sections) scattered throughout the nucleus at considerable distances (up to 4 mm) from the injection site. Significantly increased glucose utilization after intrastriatal injection of vasoactive intestinal polypeptide was observed in a number of regions (e.g., substantia nigra pars compacta, entopeduncular nucleus, lateral habenular nucleus, entorhinal, pyriform cortices, and amygdala) with known primary or secondary neuronal connections with the caudate nucleus. These alterations in glucose utilization were highly focal in nature, with the majority (40 of the 50 examined) of brain regions displaying unaltered rates of glucose utilization. The data provide evidence, obtained in conscious animals, that vasoactive intestinal polypeptide can modify functional processes in the caudate nucleus.

Animals↗
PubMed1992

Chemical implementation and thermodynamics of collective neural networks.

The chemical implementation of a neuron and connections among neurons described in prior work is used to construct collective neural networks. With stated approximations, these chemical networks are reduced to networks of the Hopfield type. Chemical networks approaching a stationary or equilibrium state provide a Liapunov function with the same extremal properties as Hopfield's energy function. Numerical comparisons of chemical and Hopfield networks with small numbers (2-16) of neurons show agreement on the results of given computations.

Catalysis↗
PubMed1998

All-or-none potentiation at CA3-CA1 synapses.

The molecular mechanisms underlying long-term potentiation in the hippocampus have received much attention because of the likely functional importance of synaptic plasticity for information storage and the development of neuronal connectivity. Surprisingly, it remains unclear whether activity modifies the strength of individual synapses in a digital (all-or-none) or analog (graded) manner. Here we characterize step-like all-or-none transitions from baseline synaptic transmission to potentiated states following protocols for inducing potentiation at putative single CA3-CA1 synaptic connections. Individual synapses appear to have all-or-none potentiation indicative of highly cooperative processes but different thresholds for undergoing potentiation. These results raise the possibility that some forms of synaptic memory may be stored in a digital manner in the brain.

Animals↗
PubMed2000

Transplanted fetal striatum in Huntington's disease: phenotypic development and lack of pathology.

Neural and stem cell transplantation is emerging as a potential treatment for neurodegenerative diseases. Transplantation of specific committed neuroblasts (fetal neurons) to the adult brain provides such scientific exploration of these new potential therapies. Huntington's disease (HD) is a fatal, incurable autosomal dominant (CAG repeat expansion of huntingtin protein) neurodegenerative disorder with primary neuronal pathology within the caudate-putamen (striatum). In a clinical trial of human fetal striatal tissue transplantation, one patient died 18 months after transplantation from cardiovascular disease, and postmortem histological analysis demonstrated surviving transplanted cells with typical morphology of the developing striatum. Selective markers of both striatal projection and interneurons such as dopamine and c-AMP-related phosphoprotein, calretinin, acetylcholinesterase, choline acetyltransferase, tyrosine hydroxylase, calbindin, enkephalin, and substance P showed positive transplant regions clearly innervated by host tyrosine hydroxylase fibers. There was no histological evidence of immune rejection including microglia and macrophages. Notably, neuronal protein aggregates of mutated huntingtin, which is typical HD neuropathology, were not found within the transplanted fetal tissue. Thus, although there is a genetically predetermined process causing neuronal death within the HD striatum, implanted fetal neural cells lacking the mutant HD gene may be able to replace damaged host neurons and reconstitute damaged neuronal connections. This study demonstrates that grafts derived from human fetal striatal tissue can survive, develop, and are unaffected by the disease process, at least for 18 months, after transplantation into a patient with HD.

Corpus Striatum↗
PubMed2000

Heparin-binding growth-associated molecule contains two heparin-binding beta -sheet domains that are homologous to the thrombospondin type I repeat.

Heparin-binding growth-associated molecule (HB-GAM) is an extracellular matrix-associated protein implicated in the development and plasticity of neuronal connections of brain. Binding to cell surface heparan sulfate is indispensable for the biological activity of HB-GAM. In the present paper we have studied the structure of recombinant HB-GAM using heteronuclear NMR. These studies show that HB-GAM contains two beta-sheet domains connected by a flexible linker. Both of these domains contain three antiparallel beta-strands. In addition to this domain structure, HB-GAM contains the N- and C-terminal lysine-rich sequences that lack a detectable structure and appear to form random coils. Studies using CD and NMR spectroscopy suggest that HB-GAM undergoes a conformational change upon binding to heparin, and that the binding occurs primarily to the beta-sheet domains of the protein. Search of sequence data bases shows that the beta-sheet domains of HB-GAM are homologous to the thrombospondin type I repeat (TSR). Sequence comparisions show that the beta-sheet structures found previously in midkine, a protein homologous with HB-GAM, also correspond to the TSR motif. We suggest that the TSR sequence motif found in various extracellular proteins defines a beta-sheet structure similar to that found in HB-GAM and midkine. In addition to the apparent structural similarity, a similarity in biological functions is suggested by the occurrence of the TSR sequence motif in a wide variety of proteins that mediate cell-to-extracellular matrix and cell-to-cell interactions, in which the TSR domain mediates specific cell surface binding.

Amino Acid Sequence↗
PubMed2001

Drosophila Ack targets its substrate, the sorting nexin DSH3PX1, to a protein complex involved in axonal guidance.

Dock, the Drosophila orthologue of Nck, is an adaptor protein that is known to function in axonal guidance paradigms in the fly including proper development of neuronal connections in photoreceptor cells and axonal tracking in Bolwig's organ. To develop a better understanding of axonal guidance at the molecular level, we purified proteins in a complex with the SH2 domain of Dock from fly Schneider 2 cells. A protein designated p145 was identified and shown to be a tyrosine kinase with sequence similarity to mammalian Cdc-42-associated tyrosine kinases. We demonstrate that Drosophila Ack (DAck) can be co-immunoprecipitated with Dock and DSH3PX1 from fly cell extracts. The domains responsible for the in vitro interaction between Drosophila Ack and Dock were identified, and direct protein-protein interactions between complex members were established. We conclude that DSH3PX1 is a substrate for DAck in vivo and in vitro and define one of the major in vitro sites of DSH3PX1 phosphorylation to be Tyr-56. Tyr-56 is located within the SH3 domain of DSH3PX1, placing it in an important position for regulating the binding of proline-rich targets. We demonstrate that Tyr-56 phosphorylation by DAck diminishes the DSH3PX1 SH3 domain interaction with the Wiskott-Aldrich Syndrome protein while enabling DSH3PX1 to associate with Dock. Furthermore, when Tyr-56 is mutated to aspartate or glutamate, the binding to Wiskott-Aldrich Syndrome protein is abrogated. These results suggest that the phosphorylation of DSH3PX1 by DAck targets this sorting nexin to a protein complex that includes Dock, an adaptor protein important for axonal guidance.

Adaptor Proteins, Signal Transducing↗
PubMed1983

Mechanisms and possible causes of Alzheimer's disease.

Alzheimer's disease has been found to be genetically transmitted. Structural changes in the disease include loss of neurons, specifically cholinergic and perhaps noradrenergic neurons. Functional connections among neurons are also lost. No cause has yet been determined, but slow viruses, autoimmune processes, and aluminum toxicity have been proposed.

Aluminum↗
PubMed2000

The tissue plasminogen activator (tPA)/plasmin extracellular proteolytic system regulates seizure-induced hippocampal mossy fiber outgrowth through a proteoglycan substrate.

Short seizure episodes are associated with remodeling of neuronal connections. One region where such reorganization occurs is the hippocampus, and in particular, the mossy fiber pathway. Using genetic and pharmacological approaches, we show here a critical role in vivo for tissue plasminogen activator (tPA), an extracellular protease that converts plasminogen to plasmin, to induce mossy fiber sprouting. We identify DSD-1-PG/phosphacan, an extracellular matrix component associated with neurite reorganization, as a physiological target of plasmin. Mice lacking tPA displayed decreased mossy fiber outgrowth and an aberrant band at the border of the supragranular region of the dentate gyrus that coincides with the deposition of unprocessed DSD-1-PG/phosphacan and excessive Timm-positive, mossy fiber termini. Plasminogen-deficient mice also exhibit the laminar band and DSD- 1-PG/phosphacan deposition, but mossy fiber outgrowth through the supragranular region is normal. These results demonstrate that tPA functions acutely, both through and independently of plasmin, to mediate mossy fiber reorganization.

Amygdala↗
PubMed2001

A conserved alpha-herpesvirus protein necessary for axonal localization of viral membrane proteins.

Pseudorabies virus, an alpha-herpesvirus, is capable of infecting the nervous system and spreading between synaptically connected neurons in diverse hosts. At least three viral membrane proteins (gE, gI, and Us9) are necessary for the spread of infection from presynaptic to postsynaptic neurons (anterograde spread) in infected rodents. To understand how these proteins effect anterograde spread between neurons, we analyzed the subcellular localization of viral proteins after infection of cultured rat sympathetic neurons with wild-type or mutant viruses. After Us9-null mutant infections but not gE-null mutant infections, only a subset of the viral structural proteins had entered axons. Surprisingly, capsid and tegument proteins but not viral membrane proteins were detected in axons. The spread of Us9 missense mutants in the rodent nervous system correlated with the amount of viral membrane proteins localized to axons. We conclude that the Us9 membrane protein controls axonal localization of diverse viral membrane proteins but not that of capsid or tegument proteins. The data support a model where virion subassemblies but not complete virions are transported in the axon. Our results provide new insight into the process of virion assembly and exit from neurons that leads to directional spread of herpesviruses in the nervous system.

Amino Acid Sequence↗
PubMed2003

Synapse formation is regulated by the signaling adaptor GIT1.

Dendritic spines in the central nervous system undergo rapid actin-based shape changes, making actin regulators potential modulators of spine morphology and synapse formation. Although several potential regulators and effectors for actin organization have been identified, the mechanisms by which these molecules assemble and localize are not understood. Here we show that the G protein-coupled receptor kinase-interacting protein (GIT)1 serves such a function by targeting actin regulators and locally modulating Rac activity at synapses. In cultured hippocampal neurons, GIT1 is enriched in both pre- and postsynaptic terminals and targeted to these sites by a novel domain. Disruption of the synaptic localization of GIT1 by a dominant-negative mutant results in numerous dendritic protrusions and a significant decrease in the number of synapses and normal mushroom-shaped spines. The phenotype results from mislocalized GIT1 and its binding partner PIX, an exchange factor for Rac. In addition, constitutively active Rac shows a phenotype similar to the GIT1 mutant, whereas dominant-negative Rac inhibits the dendritic protrusion formation induced by mislocalized GIT1. These results demonstrate a novel function for GIT1 as a key regulator of spine morphology and synapse formation and point to a potential mechanism by which mutations in Rho family signaling leads to decreased neuronal connectivity and cognitive defects in nonsyndromic mental retardation.

Actins↗
PubMedDate not supplied

Olfactory ensheathing cells: characteristics, genetic engineering, and therapeutic potential.

Injured neurons in the mammalian central nervous system (CNS) do not normally regenerate their axons after injury. Neurotrauma to the CNS usually results in axonal damage and subsequent loss of communication between neuronal networks, causing long-term functional deficits. For CNS regeneration, repair strategies need to be developed that promote regrowth of lesioned axon projections and restoration of neuronal connectivity. After spinal cord injury (SCI), cystic cavitations are often found, particularly in the later stages, due to the loss of neural tissue at the original impact site. Ultimately, for the promotion of axonal regrowth in these situations, some form of transplantation will be required to provide lesioned axons with a supportive substrate along which they can extend. Here, we review the use of olfactory ensheathing cells: their location and role in the olfactory system, their use as cellular transplants in SCI paradigms, alone or in combination with gene therapy, and the unique properties of these cells that may give them a potential advantage over other cellular transplants.

Animals↗
PubMed1999

The genetic basis of cognition.

The molecular characterization of single-gene disorders or chromosomal abnormalities that result in a cognitive abnormality (predominantly mental retardation) and of the genetic variants responsible for variation in intellectual abilities (such as IQ, language impairment and dyslexia) is expected to provide new insights into the biology of human cognitive processes. To date this hope has not been realized. Success in finding mutations that give rise to mental retardation has not been matched by advances in our understanding of how genes influence cognition. In contrast, the use of engineered mutations in mice to study models of learning and memory has cast new light on the molecular basis of memory. A comparison of studies of human and mouse mutations indicates the limitations of current genetic approaches to the understanding of human cognition. It is essential to interpret a mutation's effect within a well-characterized neural system; mutations can be used to define gene function only when the mutation has an effect on a system whose constituents form a serial causal chain, such as the molecular components of a signal transduction pathway. Typically, however, genetic mutations with a cognitive and behavioural phenotype are characterized by specific effects on different systems whose inter-relationships are unknown. Genetic approaches are currently limited to exploring neuronal function; it is not yet clear whether they will throw light on how neuronal connections give rise to cognitive processes. We need a much greater integration of different levels of understanding of cognition in order to exploit the genetic discoveries. In short, a rapprochement between molecular and systems neuroscience is required.

Animals↗
PubMed2001

Axonal surface molecules act in combination with semaphorin 3a during the establishment of corticothalamic projections.

Interactions between growing axons are considered to play important roles for the establishment of precise neuronal connections during the development of the nervous system. Here we used time-lapse imaging techniques to examine the behavior of neocortical and thalamic axons when they encounter each other in vitro. Results indicate that axonal growth cones are able to respond to specific cues expressed on the surface of fibers. Thalamic growth cones often extended along the surface of other thalamic axons and, likewise, cortical growth cones formed fascicles with cortical axons. In contrast, after contacts between cortical and thalamic fibers, in most cases growth cones collapsed and retracted from the axons. Collapse assays using membrane preparations from cortical or thalamic explants demonstrated the existence of cell-type specific collapsing factors whose activity was enhanced by a member of the semaphorin protein family, Sema3A (expressed in the thalamocortical pathway), as it increased the rate of homotypic fasciculations and at the same time amplified the segregation between cortical and thalamic axons. The interaction between axonal surface molecules and environmental cues might mediate the segregation of afferent and efferent fiber tracts in the neocortical white matter.

Animals↗
PubMed2002

Radial organization of developing preterm human cerebral cortex revealed by non-invasive water diffusion anisotropy MRI.

Cerebral cortical development involves a complex cascade of events which are difficult to visualize in intact, living subjects. In this study, we apply diffusion tensor imaging (DTI) to the evaluation of cortical development in human infants ranging from 26 to 41 weeks gestational age (GA). Apparent diffusion of water in cortex is maximally anisotropic at 26 weeks GA and anisotropy values approach zero by 36 weeks GA. During this period, the major eigenvector of the diffusion tensor in cerebral cortex is oriented radially across the cortical plate, in accord with a predominately radial deployment of its neuronal constituents. Values for the rotationally averaged water diffusion coefficient increase between 26 and 32 weeks GA, then decrease thereafter. These changes in DTI parameters are specific to cerebral cortex and reflect changes in underlying cortical architecture and formation of neuronal connections. Because of its correlation with tissue microstructure and non-invasive nature, DTI offers unique insight into cortical development in preterm human newborns and, potentially, detection of derangements of its basic cytoarchiteture.

Anisotropy↗
PubMedDate not supplied

Mechanisms of LTP induction in rat motor cortex in vitro.

The motor cortex displays remarkable plasticity in response to changes in sensory and motor experience; however, the synaptic mechanisms underlying functional plasticity are not known. It is believed that synaptic processes that alter the strength of neuronal connections, such as long-term potentiation (LTP), are mechanisms by which synaptic circuits are modified by experience, resulting in functional adaptations. In the present study, we examined the mechanisms of LTP of synaptic responses in layers II/III to vertical (stimulation in layers V/VI) and horizontal (stimulation in layers II/III) inputs, in slices from rat motor cortex. Tetanic stimulation in layers V/VI or II/III induced LTP in 60% of the field potentials (n = 20) and in 73% of the intracellularly recorded postsynaptic potentials (n = 33). LTP was induced in cells with firing patterns characteristic of regular-spiking, fast-spiking, or bursting cells. LTP was expressed, for the most part, in kainate/AMPA receptor-mediated responses; however, potentiation of NMDA receptor-mediated components was also observed. Induction of LTP was prevented when either NMDA receptors or dihydropyridine-sensitive Ca2+ channels (DSCCs) were blocked, although blockade of DSCCs was less effective in preventing LTP induction. Based on the present data and previous LTP studies, we suggest that in many forms of LTP more than one mechanism participates in the induction process. The present findings may be relevant to the synaptic mechanisms underlying functional plasticity in motor cortex.

Animals↗