Showing papers on "Nervous system published in 1998"

Axonal swellings and degeneration in mice lacking the major proteolipid of myelin

Abstract: Glial cells produce myelin and contribute to axonal morphology in the nervous system. Two myelin membrane proteolipids, PLP and DM20, were shown to be essential for the integrity of myelinated axons. In the absence of PLP-DM20, mice assembled compact myelin sheaths but subsequently developed widespread axonal swellings and degeneration, associated predominantly with small-caliber nerve fibers. Similar swellings were absent in dysmyelinated shiverer mice, which lack myelin basic protein (MBP), but recurred in MBP*PLP double mutants. Thus, fiber degeneration, which was probably secondary to impaired axonal transport, could indicate that myelinated axons require local oligodendroglial support.

Induction of monocyte chemoattractant protein-1 in HIV-1 Tat-stimulated astrocytes and elevation in AIDS dementia

Abstract: Activated monocytes release a number of substances, including inflammatory cytokines and eicosanoids, that are highly toxic to cells of the central nervous system. Because monocytic infiltration of the central nervous system closely correlates with HIV-1-associated dementia, it has been suggested that monocyte-derived toxins mediate nervous system damage. In the present study, we show that the HIV-1 transactivator protein Tat significantly increases astrocytic expression and release of monocyte chemoattractant protein-1 (MCP-1). Astrocytic release of β-chemokines, which are relatively less selective for monocytes, including RANTES, macrophage inflammatory protein-1α, and macrophage inflammatory protein-1β, was not observed. We also show that MCP-1 is expressed in the brains of patients with HIV-1-associated dementia and that, of the β-chemokines tested, only MCP-1 could be detected in the cerebrospinal fluid of patients with this condition. Together, these data provide a potential link between the presence of HIV-1 in the brain and the monocytic infiltration that may substantially contribute to dementia.

Viral infections of the nervous system.

Abstract: Part 1 General principles: historical background viruses and virus-cell interactions - nature of viruses, virus-cell interactions, virus-virus interations, effects of virus, replication of cells pathogenesis of CNS infections - experimental approaches, entry of viruses, pathways of neurinvasion, neurotropism, neurovirulence immune responses - anatomy of the immune system, immune responses to viruses, immune responses in the CNS, virus clearance from the CNS. Part 2 Acute neurological diseases: meningitis, encephalitis and poliomyelitis - general considerations, enteroviruses, mumps, adenoviruses, parvovirus, arenaviruses, filoviruses, arbviruses, differential diagnosis herpesvirus infections - varicella-zoster virus, Epstein-Barr virus, cytomegalovirus, human herpesviruses 6 and 7 rabies postinfectious demyelinating diseases - considerations of mechanisms, postinfectious enecphalomyelitis, Guillan-Barre syndrome other postviral syndromes - virus-induced encephalopahty, Reye syndrome, postpolio syndrome, chronic fatigue syndrome. Part 3 Chronic neurological diseases: chronic inflammatory and demyelinating diseases - mechanisms of virus persistence in the CNS, subacute sclerosing panencephalitis, progressive rubella panencephalitis, progresive multifocal leukoencephalopathy, possible viral cause of multiple sclerosis, possible viral cuases of other chronic inflammatory diseases retroviruses - nature of retroviruses, human T-cell lymphotrophic viruses, neurological diseases of animal retroviruses human immunodeficiency virus - human immunodeficinecy virus infections, neurological diseases, pathogenesis of neurological diseases, treatment viral infections of the developing nervous sytems - pathogenesis of foetal infections, foetal and neonatal infections in humans, viral teratogenesis in animals degenerative diseases and prions - scrapie, kuru, Creutzfeld-Jakob disease, bovine spongiform encephalopathy, possible viral causes of human degenerative diseases. Part 4 Other perspectives: cerebal tumours - pathogenesis of cell transformation by viruses, experimental production of cerebal tumous evidence for viruses in human brain tumours neurovirology afield - retinitis, labyrinthitis, myositis, vasculitis prevention and treatment - environmental control, vaccines, antiviral drugs postscripts - in defense of the white mouse, Koch's postulates revisited, emerging viral infections.

Requirement for Atm in Ionizing Radiation-Induced Cell Death in the Developing Central Nervous System

Abstract: Ataxia telangiectasia (AT) is characterized by progressive neurodegeneration that results from mutation of the ATM gene. However, neither the normal function of ATM in the nervous system nor the biological basis of the degeneration in AT is known. Resistance to apoptosis in the developing central nervous system (CNS) of Atm-/- mice was observed after ionizing radiation. This lack of death occurred in diverse regions of the CNS, including the cerebellum, which is markedly affected in AT. In wild-type, but not Atm-/- mice, up-regulation of p53 coincided with cell death, suggesting that Atm-dependent apoptosis in the CNS is mediated by p53. Further, p53 null mice showed a similar lack of radiation-induced cell death in the developing nervous system. Atm may function at a developmental survival checkpoint that serves to eliminate neurons with excessive DNA damage.

EphA4 (Sek1) receptor tyrosine kinase is required for the development of the corticospinal tract

Abstract: Members of the Eph family of tyrosine kinase receptors have been implicated in the regulation of developmental processes and, in particular, axon guidance in the developing nervous system. The function of the EphA4 (Sek1) receptor was explored through creation of a null mutant mouse. Mice with a null mutation in the EphA4 gene are viable and fertile but have a gross motor dysfunction, which is evidenced by a loss of coordination of limb movement and a resultant hopping, kangaroo-like gait. Consistent with the observed phenotype, anatomical studies and anterograde tracing experiments reveal major disruptions of the corticospinal tract within the medulla and spinal cord in the null mutant animals. These results demonstrate a critical role for EphA4 in establishing the corticospinal projection.

In situ immunodetection of activated caspase-3 in apoptotic neurons in the developing nervous system

Abstract: Activation of caspase-3 requires proteolytic processing of the inactive zymogen into p18 and p12 subunits. We generated a rabbit polyclonal antiserum, CM1, which recognizes the p18 subunit of cleaved caspase-3 but not the zymogen. CM1 demonstrated an apparent specificity for activated caspase-3 by specifically immunolabelling only apoptotic but not necrotic cortical neurons in vitro. In the embryonic mouse nervous system, CM1 immunoreactivity was detected in neurons undergoing programmed cell death and was markedly increased in Bcl-xL-deficient embryos and decreased in Bax-deficient embryos. CM1 immunoreactivity was absent in the nervous system of caspase-3-deficient mouse embryos and in neurons cultured from caspase-3-deficient mice. Along with neuronal somata, extensive neuritic staining was seen in apoptotic neurons. These studies indicate that caspase-3 is activated during apoptosis in the developing nervous system in vivo and that CM1 is a useful reagent for its in situ detection.

Chimeric brains generated by intraventricular transplantation of fetal human brain cells into embryonic rats

Abstract: Limited experimental access to the central nervous system (CNS) is a key problem in the study of human neural development, disease, and regeneration. We have addressed this problem by generating neural chimeras composed of human and rodent cells. Fetal human brain cells implanted into the cerebral ventricles of embryonic rats incorporate individually into all major compartments of the brain, generating widespread CNS chimerism. The human cells differentiate into neurons, astrocytes, and oligodendrocytes, which populate the host fore-, mid-, and hindbrain. These chimeras provide a unique model to study human neural cell migration and differentiation in a functional nervous system.

Neuronal nuclear antigen (NeuN): a marker of neuronal maturation in the early human fetal nervous system

Abstract: Neuronal nuclear antigen (NeuN) immunocytochemistry was studied in 15 normal human fetal nervous systems of 8-24 weeks gestation and in four term neonates. Material was derived from products of conception or from autopsy. Antigen retrieval was enhanced for immunocytochemistry by microwave heating of formalin-fixed paraffin sections. NeuN appears highly specific as a marker of neuronal nuclei in human fetal brain. Only rare nuclei are recognized in the germinal matrix. Cerebellar external granule cells are more strongly immunoreactive than postmigratory internal granule cells until 24 weeks gestation; by term most internal and only a few external granule cells are recognized by NeuN antibody. In the cerebrum, some reactive nuclei are demonstrated along radial glial fibers, particularly near the cortical plate. Within the cortical plate, only deep neurons (future layers 4-6) are marked at 19-22 weeks, but by 24 weeks most neurons in the cortical plate exhibit immunoreactivity, though at term some in layer 2 are still non-reactive. Some neurons fail to be recognized by NeuN at all ages: Cajal-Retzius cells, Purkinje cells, inferior olivary and dentate nucleus neurons, and sympathetic ganglion cells are examples. Despite their common origin in the cerebellar tubercle, basal pontine neurons are strongly reactive even before midgestation, hence NeuN does not predict embryonic origin. Neurons of dorsal root and cranial nerve ganglia are reactive even at 8 weeks. This study of normal fetal central nervous system provides a basis for neuropathological evaluation and as a prelude to applications in cerebral dysgeneses.

Immune Surveillance in the Injured Nervous System: T-Lymphocytes Invade the Axotomized Mouse Facial Motor Nucleus and Aggregate around Sites of Neuronal Degeneration

Abstract: Although the CNS is an established immune-privileged site, it is under surveillance by the immune system, particularly under pathological conditions. In the current study we examined the lymphocyte infiltration, a key component of this neuroimmune surveillance, into the axotomized facial motor nucleus and analyzed the changes in proinflammatory cytokines and the blood–brain barrier. Peripheral nerve transection led to a rapid influx of CD3-, CD11a (αL, LFA1α)- and CD44-immunoreactive T-cells into the axotomized mouse facial motor nucleus, with a first, low-level plateau 2–4 d after injury, and a second, much stronger increase at 14 d. These T-cells frequently formed aggregates and exhibited typical cleaved lymphocyte nuclei at the EM level. Immunohistochemical colocalization with thrombospondin (TSP), a marker for phagocytotic microglia, revealed aggregation of the T-cells around microglia removing neuronal debris. The massive influx of lymphocytes at day 14 was also accompanied by the synthesis of mRNA encoding IL1β, TNFα, and IFN-γ. There was no infiltration by the neutrophil granulocytes, and the intravenous injection of horseradish peroxidase also showed an intact blood–brain barrier. However, mice with severe combined immunodeficiency (SCID), which lack differentiated T- and B-cells, still exhibited infiltration with CD11a-positive cells. These CD11a-positive cells also aggregated around phagocytotic microglial nodules. In summary, there is a site-selective infiltration of activated T-cells into the mouse CNS during the retrograde reaction to axotomy. The striking aggregation of these lymphocytes around neuronal debris and phagocytotic microglia suggests an important role for the immune surveillance during neuronal cell death in the injured nervous system.

Progenitors of dorsal commissural interneurons are defined by MATH1 expression

Abstract: MATH1 is a neural-specific basic helix-loop-helix transcription factor. Members of this family of transcription factors are involved in the development of specific subsets of neurons in the developing vertebrate nervous system. Here we examine the cells expressing MATH1 with respect to their proliferative state and co-expression of cell-type-specific differentiation markers. We localize the MATH1 protein to the nucleus of cells in the dorsal neural tube and the external germinal layer (EGL) of the developing cerebellum. Using double-label immunofluorescence, we demonstrate that MATH1-expressing cells span both the proliferating and the differentiating zones within the dorsal neural tube, but within the EGL of the cerebellum are restricted to the proliferating zone. The early differentiating MATH1-expressing cells in the dorsal neural tube co-express TAG-1, DCC-1 and LH2, markers of dorsal commissural interneurons. In addition, transgenic mice with lacZ under the transcriptional control of MATH1-flanking DNA sequences express beta-galactosidase specifically in the developing nervous system, in a manner that mimics subsets of the MATH1-expression pattern, including the dorsal spinal neural tube. Expression of the MATH1/lacZ transgene persists in differentiated dorsal commissural interneurons. Taken together, we demonstrate MATH1 expression in a differentiating population of neuronal precursors in the dorsal neural tube that appear to give rise specifically to dorsal commissural interneurons.

DSCAM: A Novel Member of the Immunoglobulin Superfamily Maps in a Down Syndrome Region and is Involved in the Development of the Nervous System

Abstract: Down syndrome (DS), a major cause of mental retardation, is characterized by subtle abnormalities of cortical neuroanatomy, neurochemistry and function. Recent work has shown that chromosome band 21q22 is critical for many of the neurological phenotypes of DS. A gene, DSCAM (Down syndrome cell adhesion molecule), has now been isolated from chromosome band 21q22.2-22.3. Homology searches indicate that the putative DSCAM protein is a novel member of the immunoglobulin (Ig) superfamily that represents a new class of neural cell adhesion molecules. The sequence of cDNAs indicates alternative splicing and predicts two protein isoforms, both containing 10 Ig-C2 domains, with nine at the N-terminus and the tenth located between domains 4 and 5 of the following array of six fibronectin III domains, with or without the following transmembrane and intracellular domains. Northern analyses reveals the transcripts of 9.7, 8.5 and 7.6 kb primarily in brain. These transcripts are differentially expressed in substructures of the adult brain. Tissue in situ hybridization analyses of a mouse homolog of the DSCAM gene revealed broad expression within the nervous system at the time of neuronal differentiation in the neural tube, cortex, hippocampus, medulla, spinal cord and most neural crest-derived tissues. Given its location on chromosome 21, its specific expression in the central nervous system and neural crest, and the homologies to molecules involved in neural migration, differentiation, and synaptic function, we propose that DSCAM is involved in neural differentiation and contributes to the central and peripheral nervous system defects in DS.

Structure of the Planarian Central Nervous System (CNS) Revealed by Neuronal Cell Markers

Abstract: Planarians are considered to be among the most primitive animals which developed the central nervous system (CNS). To understand the origin and evolution of the CNS, we have isolated a neural marker gene from a planarian, Dugesia japonica, and analyzed the structure of the planarian CNS by in situ hybridization. The planarian CNS is located on the ventral side of the body, and composed of a mass of cephalic ganglions in the head region and a pair of ventral nerve cords (VNC). Cephalic ganglions cluster independently from VNC, are more dorsal than VNC, and form an inverted U-shaped brain-like structure with nine branches on each outer side. Two eyes are located on the dorsal side of the 3(rd) branch and visual axons form optic chiasma on the dorsal-inside region of the inverted U-shaped brain. The 6(th)-9(th) branches cluster more closely and form auricles on the surface which may function as the sensory organ of taste. We found that the gross structure of the planarian CNS along the anterior-posterior (A-P) axis is strikingly similar to the distribution pattern of the "primary" neurons of vertebrate embryos which differentiate at the neural plate stage to provide a fundamental nervous system, although the vertebrate CNS is located on the dorsal side. These data suggest that the basic plan for the CNS development along the A-P axis might have been acquired at an early stage of evolution before conversion of the location of the CNS from the ventral to the dorsal side.

Programmed cell death is a universal feature of embryonic and postnatal neuroproliferative regions throughout the central nervous system

Abstract: During central nervous system (CNS) development, programmed cell death (PCD) has been viewed traditionally as a fate reserved for differentiating neurons that are in the process of making synaptic connections. Recent studies in the embryonic cerebral cortex (Blaschke et al. [1996] Development 122:1165-1174), however, have shown that many neuroblasts in the proliferative ventricular zone undergo PCD as well and that this likely represents a novel form distinct from that found in regions of postmitotic neurons. To determine the commonality of this form of PCD throughout the CNS, the prevalence of dying cells identified by in situ end labeling plus (ISEL +; Blaschke et al. [1996]) was determined within populations of proliferating neuroblasts that were identified by rapid bromodeoxyuridine incorporation. Based on this approach, dying cells were observed to be a common feature of all proliferative neuroblast populations examined. In addition, when ISEL+ was combined with in situ hybridization for postmitotic neural gene-1 (png-1; Weiner and Chun [1997] J. Comp. Neurol. 381:130-142), which identifies newly postmitotic neurons, a positive correlation was found between the start of differentiation and the onset of PCD. These data indicate that PCD in neuroblast proliferative zones is a universal feature of nervous system development. Moreover, cell death represents a prominent cell fate that may be linked to mechanisms of differentiation.

Neuroanatomical and Neurophysiological Mechanisms Involved in Central Nervous System Dysfunctions Induced by Prenatal Alcohol Exposure

Abstract: One of the most severe consequences of maternal ethanol consumption is the damage to the developing central nervous system, which is manifested by long-term cognitive and behavioral deficits in the offspring. Prenatal exposure to ethanol affects many crucial neurochemical and cellular components of the developing brain. Ethanol interferes with all of the stages of brain development, and the severity of the damage depends on the amount of ethanol intake and level of exposure. Experimental observations also indicate that the toxic effects of ethanol are not uniform : some brain regions are more affected than others and, even within a given region, some cell populations are more vulnerable than others. The neocortex, the hippocampus, and the cerebellum are the regions in which the neurotoxic effects of ethanol have been associated with the behavioral deficits. At the cellular level, ethanol disrupts basic developmental processes, including interference with division and proliferation, cell growth, and differentiation and the migration of maturing cells. Alterations in astroglia development and in neuronal-glial interactions may also influence the development of the nervous system. An impairment of several neurotransmitter systems and/or their receptors, as well as changes in the endocrine environment during brain development, are also important factors involved in the behavioral dysfunctions observed after prenatal ethanol exposure. Finally, some molecular mechanisms of ethanol-induced behavioral dysfunctions will be discussed.

Nervous System Defects of AnkyrinB (−/−) Mice Suggest Functional Overlap between the Cell Adhesion Molecule L1 and 440-kD AnkyrinB in Premyelinated Axons

Abstract: The L1 CAM family of cell adhesion molecules and the ankyrin family of spectrin-binding proteins are candidates to collaborate in transcellular complexes used in diverse contexts in nervous systems of vertebrates and invertebrates. This report presents evidence for functional coupling between L1 and 440-kD ankyrinB in premyelinated axons in the mouse nervous system. L1 and 440-kD ankyrinB are colocalized in premyelinated axon tracts in the developing nervous system and are both down-regulated after myelination. AnkyrinB (−/−) mice exhibit a phenotype similar to, but more severe, than L1 (−/−) mice and share features of human patients with L1 mutations. AnkyrinB (−/−) mice exhibit hypoplasia of the corpus callosum and pyramidal tracts, dilated ventricles, and extensive degeneration of the optic nerve, and they die by postnatal day 21. AnkyrinB (−/−) mice have reduced L1 in premyelinated axons of long fiber tracts, including the corpus callosum, fimbria, and internal capsule in the brain, and pyramidal tracts and lateral columns of the spinal cord. L1 was evident in the optic nerve at postnatal day 1 but disappeared by postnatal day 7 in mutant mice while NCAM was unchanged. Optic nerve axons of ankyrinB (−/−) mice become dilated with diameters up to eightfold greater than normal, and they degenerated by day 20. These findings provide the first evidence for a role of ankyrinB in the nervous system and support an interaction between 440-kD ankyrinB and L1 that is essential for maintenance of premyelinated axons in vivo.

Functional Evidence that BDNF Is an Anterograde Neuronal Trophic Factor in the CNS

Abstract: In this report, we have tested the hypothesis that brain-derived neurotrophic factor (BDNF) is an anterograde neurotrophic factor in the CNS and have focused on central noradrenergic neurons that synthesize BDNF. Double-label immunocytochemistry for BDNF and dopamine-beta-hydroxylase (DBH), a marker for noradrenergic neurons, demonstrated that BDNF is partially localized to noradrenergic nerve fibers and terminals in the adult rat brain. To test the functional importance of this anterograde BDNF, we analyzed transgenic mice carrying a DBH-BDNF minigene. Increased synthesis of BDNF in noradrenergic neurons of DBH-BDNF mice caused elevated TrkB tyrosine kinase activation throughout postnatal life in the neocortex, a noradrenergic target region. This afferently regulated increase in TrkB receptor activity led to long-lasting alterations in cortical morphology. To determine whether noradrenergic neuron-expressed BDNF also anterogradely regulated neuronal survival, we examined a second noradrenergic target, neonatal facial motoneurons. One week after axotomy, 72% of facial motoneurons were lost in control animals, whereas only 30-35% were lost in DBH-BDNF transgenic mice. Altogether, these results indicate that BDNF is anterogradely transported to fibers and terminals of noradrenergic neurons, that anterogradely secreted BDNF causes activation of TrkB in target regions, and that this secretion has functional consequences for target neuron survival and differentiation. This presynaptic secretion of BDNF may provide a cellular mechanism for modulating neural circuitry, in either the developing or mature nervous system.

Absence of the Mid-sized Neurofilament Subunit Decreases Axonal Calibers, Levels of Light Neurofilament (NF-L), and Neurofilament Content

Abstract: Neurofilaments (NFs) are prominent components of large myelinated axons and probably the most abundant of neuronal intermediate filament proteins. Here we show that mice with a null mutation in the mid-sized NF (NF-M) subunit have dramatically decreased levels of light NF (NF-L) and increased levels of heavy NF (NF-H). The calibers of both large and small diameter axons in the central and peripheral nervous systems are diminished. Axons of mutant animals contain fewer neurofilaments and increased numbers of microtubules. Yet the mice lack any overt behavioral phenotype or gross structural defects in the nervous system. These studies suggest that the NF-M subunit is a major regulator of the level of NF-L and that its presence is required to achieve maximal axonal diameter in all size classes of myelinated axons.

Developmentally Regulated Spontaneous Activity in the Embryonic Chick Retina

Abstract: Even before birth and the onset of sensory experience, neural activity plays an important role in shaping the vertebrate nervous system. In the embryonic chick visual system, activity in the retina before vision has been implicated in the refinement of retinotopic maps, the elimination of transient projections, and the survival of a full complement of neurons. In this study, we report the detection of a physiological substrate for these phenomena: waves of spontaneous activity in the ganglion cell layer of the embryonic chick retina. The activity is robust and highly patterned, taking the form of large amplitude, rhythmic, and wide-ranging waves of excitation that propagate across the retina. Activity waves are most prominent and organized between embryonic days 13–18, coinciding with the developmental period during which retinal axons refine their connections in their targets. The spatial and temporal features of the patterns observed are consistent with the role of activity patterns in shaping eye-specific projections and retinotopic maps but inconsistent with the hypothesis that they specify lamina-specific projections in the tectum. Antagonists of glutamatergic and glycinergic transmission and of gap junctional communication suppress spontaneous activity, whereas antagonists to GABAergic transmission potentiate it. Based on these results, we propose that spontaneous activity in the ganglion cells is regulated by chemical inputs from both bipolar and amacrine cells and by gap junctional coupling involving ganglion cells.

Cellular correlates of long-term sensitization in Aplysia.

Abstract: Although in vitro analyses of long-term changes in the sensorimotor connection of Aplysia have been used extensively to understand long-term sensitization, relatively little is known about the ways in which the connection is modified by learning in vivo . Moreover, sites other than the sensory neurons might be modified as well. In this paper, several different biophysical properties of sensory neurons, motor neurons, and LPl17, an identified interneuron, were examined. Membrane properties of sensory neurons, which were expressed as increased excitability and increased spike afterdepolarization, were affected by the training. The biophysical properties of motor neurons also were affected by training, resulting in hyperpolarization of the resting membrane potential and a decrease in spike threshold. These results suggest that motor neurons are potential loci for storage of the memory in sensitization. The strength of the connection between sensory and motor neurons was affected by the training, although the connection between LPl17 and the motor neuron was unaffected. Biophysical properties of LPl17 were unaffected by training. The results emphasize the importance of plasticity at sensory–motor synapses and are consistent with the idea that there are multiple sites of plasticity distributed throughout the nervous system.