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PubMed2000

Spatial considerations for stimulus-dependent transcription in neurons.

Most neurons have elaborate dendrites as well as an axon emanating from the cell body that form synaptic connections with one or many target cells, which may be located a considerable distance from the cell body. Such complex and impressive morphologies allow some types of neurons to integrate inputs from one to many thousands of pre-synaptic partners and to rapidly propagate electrical signals, often over long distances, to post-synaptic target cells. Much slower, non-electrical signals also propagate from dendrites and distal axons to neuronal nuclei that influence survival, growth, and plasticity. The distances between distal dendrites and/or distal axons and cell bodies of neurons can be hundreds of microns to more than one meter. This long-range biochemical signal propagation from distal dendrites and distal axons to neuronal nuclei is entirely unique to neurons. This review is focused on excitatory neurotransmitter signaling from dendritic synapses to neuronal nuclei as well as on retrograde growth factor signaling from distal axons to neuronal nuclei.

Animals↗
PubMed2006

Cross-linking cell surface chemokine receptors leads to isolation, activation, and differentiation of monocytes into potent dendritic cells.

Monocytes express on the cell surface several kinds of chemokine receptors that facilitate chemotaxis followed by differentiation in target tissues. In the present study, we found that a large number of monocytes from peripheral blood mononuclear cells (PBMCs) tightly adhered to plastic cell culture plates precoated with a monoclonal antibody (mAb, clone T312) specific for human CCR5 but not an isotype control after overnight incubation. Soluble T312 did not induce such adhesion, indicating that cross-linking of CCR5 is required for the enhanced adhesion of monocytes. The adhesion was blocked by a PI3-K inhibitor and an anti-CD18 blocking mAb. Following the cross-linking of CCR5, monocytes synthesized high levels of M-CSF, RANTES, MIP-1 alpha, and MIP-1 beta associated with a readily detectable down modulation of CD14, CD4, CCR5, and CXCR4 expression. The T312-enriched monocytes differentiated into dendritic cells (DCs) in the presence of interleukin-4 alone. After maturation with beta-interferon, the T312-induced DCs stimulated proliferation of allogeneic naïve CD4(+) T cells accompanied by the synthesis of high levels of gamma-interferon in vitro. Furthermore, the T312-induced DCs were capable of stimulating antigen-specific human T- and B-cell immune responses in our hu-PBL-SCID mouse system. Finally, screening of other anti-chemokine receptor mAbs showed that select clones of mAbs against CXCR4 and CCR3 were also capable of facilitating enrichment of monocytes similar to T312. These results show that cross-linking of chemokine receptors on monocytes by appropriate mAbs leads to activation and differentiation of monocytes and that the method described herein provides an alternate simple strategy for adherence-based isolation of monocytes and generation of functional DCs.

Animals↗
PubMed1999

5-HT1B receptor knock-out mice exhibit increased exploratory activity and enhanced spatial memory performance in the Morris water maze.

In an attempt to characterize the contribution of the 5-HT1B receptor to behavior, 5-HT1B knock-out (KO) mice were subjected to a battery of behavioral paradigms aimed at differentiating various components of cognitive and emotional behaviors. In an object exploration task, wild-type (WT) and 5-HT1B KO mice did not differ in locomotor activity. 5-HT1B KO mice, however, displayed lower thigmotaxis (an index of anxiety) associated with a higher level of object exploratory activity, but no genotype differences were observed in the elevated plus maze. 5-HT1B KO mice also displayed a lack of exploratory habituation. In the spatial version of the Morris water maze, 5-HT1B KO mice showed higher performances in acquisition and transfer test, which was not observed in the visual version of the task. No genotype differences were found in contextual fear conditioning, because both WT and 5-HT1B KO mice were able to remember the context where they had received the aversive stimulus. The deletion of the 5-HT1B receptor, associated with appropriate behavioral paradigms, thus allowed us to dissociate anxiety from response to novelty, and perseverative behavior (lack of habituation) from adaptive behavioral inhibition underlying cognitive flexibility (transfer stage in the water maze). The deletion of the 5-HT1B receptor did not result in significant developmental plasticities for other major 5-HT receptor types but may have influenced other neurotransmission systems. The 5-HT1B receptor may be a key target for serotonin in the modulation of cognitive behavior, particularly in situations involving a high cognitive demand.

Analysis of Variance↗
PubMed1992

GAP-43 as a modulator of G protein transduction in the growth cone.

Much circumstantial evidence that GAP-43 is involved in neuronal growth cone function has accumulated over the last ten years. The expression of the protein is closely correlated both temporally and spatially with periods of axonal outgrowth, and the protein is highly concentrated in the growth cone membrane. There is direct evidence that overexpression of the protein can alter cell shape. This review focuses on the molecular mechanisms whereby GAP-43 could exert these actions. One important requirement for GAP-43 function is its localization to appropriate regions of the cell. The ability of this hydrophilic protein to associate with membrane fractions is determined by a short 10 amino acid stretch of the amino terminus of the protein, which contains two cysteine residues subject to palmitoylation. Whether this region can direct growth cone targeting in neurons is not yet clear. Once appropriately localized, GAP-43 may modulate complex cellular properties such as growth cone motility, synaptic plasticity and neurotransmitter release. One possible molecular mechanism for these cellular changes in GAP-43 regulation of the GTP-binding protein, G(o). The observation that the growth cone membrane contains extremely high concentrations of G(o) led us to investigate the interaction of G(o) and GAP-43. There is evidence that G protein-mediated transduction systems can control the same cellular functions thought to be altered by GAP-43: growth cone motility, neurotransmitter release and synaptic plasticity. Purified GAP-43 does stimulate guanine nucleotide binding to G(o). Its action in stimulating GDP release is quite similar to that of G protein-coupled transmembrane receptors.(ABSTRACT TRUNCATED AT 250 WORDS)

Acylation↗
PubMed2002

Osteocytes: a proposed multifunctional bone cell.

Most cell types are ascribed a single function. The osteoclast holds the unique distinction of performing only one function in the body - that of resorbing bone. The osteoblast has been ascribed the major function of bone matrix production. Other less well-defined cell types include progenitor cells and the nebulous cell type that can support osteoclast formation upon stimulation with various bone resorbing cytokines. Obviously, these cells could have other functions. The definition of an osteocyte is descriptive of its location - cells surrounded by mineralized matrix - not its function. For this year's Sun Valley Workshop on osteocytes, several proposed functions will be presented. First, a general consensus exists that osteocytes are most likely sensitive to mechanotransduction and translate mechanical strain into biochemical signals. Consensus does not exist on the nature of the mechanical strain, the form of the biochemical signals, the target cell(s), or the viability status of the osteocyte. Second, it is also proposed that this cell is incredibly adaptable and expresses plasticity in response to mechanical stimuli. In other words, this cell can readjust its responses to strain in the presence of other bone agents such as hormones and bone factors. Third, it will also be presented that osteocytes maintain systemic mineral homeostasis by regulating mineral release and deposition over the enormous surface area over which these cells interface with the surrounding matrix. Although osteocytes are terminally differentiated osteoblasts, they appear to have separate and distinct properties from their predecessors. Bone cell biologists loaded with an arsenal of bone anabolic and catabolic factors are examining the expression and effects of these factors on osteocytes. Engineers trained in mathematical modeling have generated new models of strain and connectivity to be tested. The unique morphology of osteocytes suggests that the cytoskeleton in these cells may function differently from osteoblasts and other cell types. Osteocytes may consist of different subpopulations; some that possess receptors for parathyroid hormone (PTH) and others that only express receptors for carboxyl terminal PTH suggesting different functions and responses. Osteocytes may respond rapidly to strain through glutamate receptor-like mechanisms, through calcium influxes, through gap junctions, and less rapidly through the production of small molecules and factors. Strain may take the form of substrate stretching and/or fluid flow. Osteocytes may communicate with other osteocytes and/or bone surface cells such as lining cells, stromal cells, osteoblasts, and/or osteoclasts and their precursors. The viability status of the osteocyte may determine the type of signals sent from these cells. If the cells are deprived of oxygen or nutrients, the apoptotic cells may send signals for initiation of resorption. If the cells and/or their dendritic process are ripped or torn by microdamage, they may send signals of both resorption and formation. If the majority of these theories are correct, then the osteocyte is the 'smart' cell that can direct or orchestrate the bone resorbing and bone forming cells even in its death and dying.

Journal Article↗
PubMed1995

ADP-ribosylation as a mechanism for the action of nitric oxide in the nervous system.

Nitric oxide (NO.) is a unique biological messenger molecule in the central and peripheral nervous systems. The molecular targets of NO. are expanding, as are its physiologic and pathophysiologic roles in the nervous system. NO. may play a role in synaptic plasticity and nervous system morphogenesis and regulate neurotransmitter release and gene expression. It functions as a nonadrenergic, noncholinergic neurotransmitter in the gastrointestinal tract, where it mediates peristalsis through smooth muscle relaxation, and in the penis, where it regulates erectile function. NO. is emerging as an important endogenously derived neurotoxin that may contribute to neuronal cell death in a variety of disorders of the nervous system. NO. may mediate its neurotoxic properties through DNA damage and the subsequent activation of poly (ADP-ribose) synthetase which depletes neurons of their energy stores.

Adenosine Diphosphate Ribose↗
PubMed1994

Rapid sprouting of filopodia in nerve terminals of chromaffin cells, PC12 cells, and dorsal root neurons induced by electrical stimulation.

Rapid morphological changes induced by direct electrical stimulation of nerve terminals were studied by using video-enhanced differential interference contrast microscopy at a very high magnification (12,000x). We used mainly cultured bovine chromaffin cells, which developed neurite-like processes, and PC12 cells, which showed neuronal differentiation upon NGF treatment. In a few cases, primary neurons of the rat dorsal root ganglion were also examined. Brief pulse stimulation of the terminals and varicosities induced exocytosis accompanied by rapid formation of filopodia. These filopodia, 0.1-0.2 micron in diameter and up to 10 microns in length, formed within a few hundreds of milliseconds and then retracted within tens of seconds. They could also be induced by K depolarization. This rapid filopodial sprouting strongly depended on the presence of extracellular Ca2+ and could be abolished in a medium containing a Ca chelator (EGTA) or La2+. Anti-cytoskeletal agents colchicine and cytochalasin B failed to block this response completely but lidocaine fully suppressed it. Quantitative analysis of exocytosis and filopodial sprouting showed that they were independent events, not directly linked to each other, having different thresholds usually higher for filopodial formation. In PC12 cells, the extent of filopodial sprouting varied with the state of differentiation of the cells, suggesting a functional role of rapid sprouting during a particular phase of their differentiation. Filopodia could be induced with greater ease by repetitive stimulation. The same responses may occur at growth cones approaching the target cells or even at mature synapses particularly after repetitive electrical activity, possibly playing a role in use-dependent synapse formation or plasticity.

Aging↗
PubMed1996

LPS induces NK1.1+ alpha beta T cells with potent cytotoxicity in the liver of mice via production of IL-12 from Kupffer cells.

We recently reported that systemic administration of IL-12 into mice activates NK1.1+ alpha beta T cells with intermediate TCR (NK1+TCRint) and induces strong MHC-unrestricted cytotoxicity in C57BL/6 mice. In the present report, we examined the effect of LPS on Kupffer cells and NK1+TCRint, cells in C57BL/6 mice. Administration of LPS, as well as synthetic lipid A analogue (ONO-4007), but not detoxified LPS, induces the increase of NK1 expression of NK1+TCRint cells (NKlhighTCRint) and the acquisition of strong MHC-unrestricted cytotoxicity of these cells against NK-sensitive and NK-resistant targets as does IL-12 administration. LPS as well as ONO-4007 induced IL-12 mRNA in hepatic mononuclear cells, mainly in plastic-adherent Kupffer cells. LPS-induced cytotoxicity of hepatic mononuclear cells was greatly reduced by in vivo injections of anti-IL-12 Ab, to a lesser extent by anti-IFN-gamma Ab, but not by anti-IL-1 nor anti-TNF-alpha Ab. Pretreatment of mice with LPS induced inhibition of hepatic metastases of i.v. injected EL4 cells in C57BL/6 euthymic and athymic mice and this antimetastasis was inhibited by injection of anti-IL-12 Ab. This antimetastatic effect of LPS in the liver was also observed in different strains of mice and tumors, In contrast to IL-12, however, LPS was not so effective when administered after tumor inoculation. These results revealed that LPS (lipid A) stimulates NK1+TCRint cells through IL-12 production from Kupffer cells and suggest that bacterial components, probably including those from intestine, are activators of Kupffer cells and NK1+TCRint, cells in the liver. It is also suggested that the host condition as well as LPS-induced cytokines other than IL-12 may affect antitumor effect induced by LPS in the liver.

Animals↗
PubMedDate not supplied

The role of metabotropic glutamate receptor 5 in learning and memory processes.

Metabotropic glutamate receptor 5 (mGluR5), a subtype in the group I mGluRs, couples to phospholipase C through Gq protein. Stimulation of mGluR5 leads to the release of calcium from intracellular stores and protein kinase C activation. In addition, links to different ion channels and other signaling mechanisms have also been revealed. MGluR5s are mainly localized postsynaptically on the periphery of synap-ses. MGluR5s have been implicated in synaptic plasticity and learning and memory. The development of the highly potent and selective mGluR5 antagonist 2-methyl-6-(phenylethynyl)-pyridine (MPEP) has facilitated the understanding of the roles of mGluR5s in the central nervous system. Both in vitro and in vivo studies have demonstrated that the activation of mGluR5s is necessary for some forms of long-term potentiation and long-term depression in different brain regions. Investigations of the effects of MPEP in various behavioral paradigms have concluded that mGluR5s play a critical role in aversive learning tasks and in hippocampal-dependent spatial learning. However, MPEP has proved ineffective in certain other learning tasks. MGluR5 knockout mice have shown impairments in water maze and radial arm maze performance as well as in contextual fear conditioning, but not in cue conditioning. This review summarizes recent advances reported on mGluR5 function in synaptic plasticity, learning and memory. The current development of positive and negative allosteric modulators of mGluR5 will provide new pharmacological tools to enhance our knowledge of these receptors in physiological and pathophysiological processes and will further facilitate new investigations on mGluR5 as a therapeutic target for a range of neurological and psychological disorders.

Animals↗
PubMed1999

Dynamic regulation of cpg15 during activity-dependent synaptic development in the mammalian visual system.

During visual system development, neural activity regulates structural changes in connectivity including axonal branching and dendritic growth. Here we have examined a role for the candidate plasticity gene 15 (cpg15), which encodes an activity-regulated molecule that can promote dendritic growth, in this process. We report that cpg15 is expressed in the cat visual system at relatively high levels in the lateral geniculate nucleus (LGN) but at very low levels in its synaptic target, layer 4 of the visual cortex. Prenatally, when cpg15 mRNA in the LGN is most abundant, expression is insensitive to action potential blockade by tetrodotoxin. Postnatally, activity regulation of cpg15 emerges in the LGN coincident with development of ocular dominance columns in the visual cortex. cpg15 can be detected in layers 2/3 and 5/6 of visual cortex postnatally, and expression in layers 2/3 is activity-regulated during known periods of activity-dependent plasticity for these layers. Localization and regulation of cpg15 expression in the visual system are consistent with a presynaptic role for CPG15 in shaping dendritic arbors of target neurons during activity-dependent synaptic rearrangements, both in development and adulthood.

Action Potentials↗
PubMed1998

Polysialic acid at the cell surface: biophysics in service of cell interactions and tissue plasticity.

Polysialic acid (PSA) is a long polymer of negatively-charged sialic acid associated with the neural cell adhesion molecule. PSA serves as a potent negative regulator of cell interactions via its unusual biophysical properties. During development the abundant and regulated expression of this carbohydrate is closely correlated with axon pathfinding and targeting, and with certain aspects of muscle formation. Its level can also be modulated by synaptic activity. PSA expression is more restricted in the neonatal and adult brain, being primarily associated with regions capable of morphological or physiological changes. Studies on the function of PSA studies suggest that its primary role is to promote developmentally-controlled and activity-dependent plasticity in cell interactions and thereby facilitate changes in the structure and function of the nervous system. The presence of PSA on a variety of metastatic tumor lines has also attracted the attention of oncologists, and its late appearance in evolution raises interesting questions about the phylogeny of complex tissue formation.

Adult↗
PubMed2005

[Spectrometric assessment of thyroid depth within the radioiodine test].

UNLABELLED: Aim of this study is the validation of a simple method for evaluating the depth of the target volume within the radioiodine test by analyzing the emitted iodine-131 energy spectrum. PATIENTS, METHODS: In a total of 250 patients (102 with a solitary autonomous nodule, 66 with multifocal autonomy, 29 with disseminated autonomy, 46 with Graves' disease, 6 for reducing goiter volume and 1 with only partly resectable papillary thyroid carcinoma), simultaneous uptake measurements in the Compton scatter (210 +/- 110 keV) and photopeak (364-45/+55 keV) windows were performed over one minute 24 hours after application of the 3 MBq test dose, with subsequent calculation of the respective count ratios. Measurements with a water-filled plastic neck phantom were carried out to perceive the relationship between these quotients and the average source depth and to get a calibration curve for calculating the depth of the target volume in the 250 patients for comparison with the sonographic reference data. Another calibration curve was obtained by evaluating the results of 125 randomly selected patient measurements to calculate the source depth in the other half of the group. RESULTS: The phantom measurements revealed a highly significant correlation (r = 0,99) between the count ratios and the source depth. Using these calibration data, a good relationship (r = 0,81, average deviation 6 mm corresponding to 22%) between the spectrometric and the sonographic depths was obtained. When using the calibration curve resulting from the 125 patient measurements, the overage deviation in the other half of the group was only 3 mm (12%). There was no difference between the disease groups. CONCLUSION: The described method allows on easy to use depth correction of the uptake measurements providing good results.

Carcinoma, Papillary↗
PubMed1998

Extraperoxisomal targets of peroxisome proliferators: mitochondrial, microsomal, and cytosolic effects. Implications for health and disease.

Peroxisome proliferators are a structurally diverse group of compounds that include the fibrate hypolipidemic drugs, the phthalate ester industrial plasticizers, the phenoxy acid herbicides, and the anti-wetting corrosion inhibitors perfluorinated straight-chain monocarboxylic fatty acids. Administration of these chemicals to rodents results in a number of effects, the most prominent being hepatomegaly and induction of peroxisomal enzyme activities. Several of these compounds have also been associated with the production of liver tumors in rodents and are classified as nongenotoxic hepatocarcinogens. Experimental evidence suggests that humans are not susceptible to these effects following exposure to peroxisome-proliferating compounds. This has led to the proposal that an "actual threat to humans" from exposure to one of these compounds seems "rather unlikely". Indeed, recent reports suggest that peroxisome proliferators may prove valuable as antitumor agents in humans. However, this assessment is preliminary given that peroxisome proliferators also produce a myriad of extraperoxisomal effects in livers and other tissues of experimental animals. Such effects include both stimulation and inhibition of mitochondrial and microsomal metabolism and alteration of the activities of various cytosolic enzymes. These responses may be directly or indirectly related to the effects on peroxisomes or may be totally independent of these events. Whether the extraperoxisomal effects of these compounds occur in humans is not known and their potential impact on human health remains to be investigated.

Animals↗
PubMed2006

Smurf1 regulates tumor cell plasticity and motility through degradation of RhoA leading to localized inhibition of contractility.

Rho GTPases participate in various cellular processes, including normal and tumor cell migration. It has been reported that RhoA is targeted for degradation at the leading edge of migrating cells by the E3 ubiquitin ligase Smurf1, and that this is required for the formation of protrusions. We report that Smurf1-dependent RhoA degradation in tumor cells results in the down-regulation of Rho kinase (ROCK) activity and myosin light chain 2 (MLC2) phosphorylation at the cell periphery. The localized inhibition of contractile forces is necessary for the formation of lamellipodia and for tumor cell motility in 2D tissue culture assays. In 3D invasion assays, and in in vivo tumor cell migration, the inhibition of Smurf1 induces a mesenchymal-amoeboid-like transition that is associated with a more invasive phenotype. Our results suggest that Smurf1 is a pivotal regulator of tumor cell movement through its regulation of RhoA signaling.

Animals↗
PubMed1996

Bone extracellular matrix induces homeobox proteins independent of androgens: possible mechanism for androgen-independent growth in human prostate cancer cells.

BACKGROUND: Differences in gene expression in prostate cells are believed to be secondary to epithelial-stromal interactions. We theorized that bone matrix may provide a fertile "soil" for prostate cancer by inducing androgen-dependent genes and allowing for androgen-independent growth. METHODS: Human prostate cancer cells (LNCaP) were grown under different conditions and analyzed for differential expression of mRNA. LNCaP cells were grown in the presence of 10 nM dihydrotestosterone (DHT), on extracellular matrix (ECM) derived from bone cells (without exogenous DHT), and on plastic culture dishes without exogenous DHT. A differential display of mRNA produced by LNCaP cells grown in the above conditions was then analyzed. RESULTS: Multiple unique transcripts were present in cells that were grown in the presence of DHT and on bone ECM (without exogenous DHT), but not on plastic culture dishes without exogenous DHT. Nine of these transcripts were then cloned and analyzed. Many (5/9) of these transcripts were found to contain multiple ATTA motifs in their corresponding 3'-untranslated regions. ATTA motifs have been shown to be homeobox protein-binding sites. Homeobox proteins and their target genes are thought to regulate cellular differentiation. Consistent with this, we demonstrated by reverse transcription polymerase chain reaction (PCR) that homeobox genes were differentially expressed in LNCaP cells when the cells were grown in the presence of DHT and on bone ECM (without exogenous DHT), but not on plastic culture dishes without exogenous DHT. Furthermore, we assayed LNCaP/fetal fibroblast chimeric tumors (n = 8) that were grown in male nude mice. Some of these tumors continued to grow in these mice despite treatment with surgical castration. In blinded studies, we were able to determine which tumor samples were androgen independent by their expression of homeobox genes. All samples that were androgen independent (n = 4) expressed the homeobox genes. Finally, gel retardation assay demonstrated that the homeobox proteins were able to bind to our cloned DNA sequences. Furthermore, footprinting analysis showed that the homeobox proteins bound to the ATTA motif in the 3'-region of our target DNA. CONCLUSIONS: Bone ECM, in the absence of DHT, has the ability to regulate androgen-responsive genes. Furthermore, many of these genes contain homeobox binding sites and the expression of homeobox genes may itself be regulated by bone ECM. If so, this may partially explain the clinical observation that bone provides a fertile "soil" for prostate cancer growth and metastasis.

Adenine↗
PubMed2003

Near simultaneous computed tomography image-guided stereotactic spinal radiotherapy: an emerging paradigm for achieving true stereotaxy.

PURPOSE: To report treatment setup data from an emerging technique using near-simultaneous computed tomography (CT) image-guided stereotactic radiotherapy for the treatment of spinal and paraspinal tumors. METHODS AND MATERIALS: A targeting system that integrates a CT-on-rails scanner with a linear accelerator (LINAC) was evaluated in the lead-in portion of a Phase I/II protocol for treating patients with paraspinal metastases. Patients were immobilized in supine position by a moldable body cushion vacuum wrapped with a plastic fixation sheet. Planning CT and immediately repeated CT were performed on the LINAC/CT-on-rails unit to assess respiratory-related vertebral body motion. Coplanar intensity-modulated radiotherapy (IMRT) using 7-9 beams was used to deliver 30 Gy in five fractions to the target volume, while limiting the spinal cord dose to <10 Gy. Pretreatment CT scans were fused with the planning CT scans to determine the correct target isocenter by accounting for any translational and roll (axial) rotational discrepancies from the planning CT. (Corrections caused by yaw and pitch rotations have not yet been implemented.) The reproducibility of the treatment isocenter as compared with the planned isocenter was measured with digitally reconstructed radiographs (DRRs), portal film imaging, and immediate post-treatment verification CT scans. Phantom measurements were taken for dose verification for each IMRT plan. RESULTS: Based on a total of 36 CT scans (3 for planning, 3 for respiration study, 15 pretreatment, and 15 post-treatment) from 3 patients, no respiration-associated vertebral body motion was seen. A comparison of the corrected daily anterior-posterior (AP) and lateral (LAT) digital portal images with the planning AP and LAT DRRs confirmed that the isocenter setup accuracy for the 15 treatments was within 1 mm of the planning isocenter. The results from the immediate post-treatment CT scans reconfirmed the findings from the portal images and verified the absence of spinal movement during the treatment. The ion-chamber measurement for the high-dose region was within 2% of the planning dose for three patient treatment plans. Film dose measurement in an IMRT quality assurance phantom demonstrated good agreement from 90% to 30% isodose lines between the planned and measured results. CONCLUSION: Preliminary experience suggests that the near-simultaneous CT image-guided verification technique can be used as a new platform technology for extracranial applications of stereotactic radiotherapy and radiosurgery to spinal and paraspinal tumors.

Equipment Design↗
PubMed2005

Functional plasticity or vulnerability after early brain injury?

CONTEXT: Traumatic brain injury (TBI) is a common, acquired, childhood disability that may be used as a model to understand more completely the impact of early brain injury on both brain structure and day-to-day function. Contrary to previously held views of the "plasticity" of the young brain, recent research suggests that such early insults may have a profound impact on development. To date, these suggestions remain largely untested. OBJECTIVES: To plot changes in cognitive abilities after childhood TBI over the 30 months after injury and to examine the impact of age at injury on cognitive outcomes. DESIGN: Prospective longitudinal study. SETTING: Royal Children's Hospital, Victoria, Australia. MAIN OUTCOME MEASURES: Global intellectual ability, verbal and nonverbal skills, attention, and processing speed. PARTICIPANTS: A total of 122 children admitted to the hospital with a diagnosis of TBI were divided according to injury age, ie, young (age: 3-7 years) or old (age: 8-12 years), and injury severity (mild, moderate, or severe) and were evaluated acutely and at 12 and 30 months after injury. An additional sample of children injured before 3 years of age (n = 27) was compared with these groups with respect to global intellectual ability only. RESULTS: A clear relationship was documented between injury severity and cognitive performance. For children who sustained severe injury, younger age at injury was associated with minimal, if any, recovery after injury, but better outcomes were observed after severe TBI among older children. Age at injury was not predictive of outcomes for children with mild or moderate TBI, although infants (age: 0-2.11 years) with moderate TBI showed poorer outcomes than did older children with injury of similar severity. CONCLUSIONS: Findings support a "double-hazard" model for severe and early brain insults and add to the ongoing debate regarding cerebral plasticity, suggesting that, contrary to traditional views, young children who sustain severe TBI in early childhood or moderate or severe TBI in infancy may be particularly vulnerable to significant residual cognitive impairment. From a clinical perspective, results indicate that long-term follow-up monitoring and management should be targeted to this high-risk group.

Brain Injuries↗
PubMed2005

Experience-driven plasticity of visual cortex limited by myelin and Nogo receptor.

Monocular deprivation normally alters ocular dominance in the visual cortex only during a postnatal critical period (20 to 32 days postnatal in mice). We find that mutations in the Nogo-66 receptor (NgR) affect cessation of ocular dominance plasticity. In NgR-/- mice, plasticity during the critical period is normal, but it continues abnormally such that ocular dominance at 45 or 120 days postnatal is subject to the same plasticity as at juvenile ages. Thus, physiological NgR signaling from myelin-derived Nogo, MAG, and OMgp consolidates the neural circuitry established during experience-dependent plasticity. After pathological trauma, similar NgR signaling limits functional recovery and axonal regeneration.

Animals↗