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PubMed1992

Conduction properties of spinal cord axons in the myelin-deficient rat mutant.

Spinal cords of myelin-deficient and normal age-matched (control) rats were removed and their conduction and pharmacological properties studied in an in vitro brain slice chamber. The conduction velocity of the myelin-deficient dorsal column axons was reduced to about 25% of control axons; however, the amyelinated myelin-deficient axons displayed refractory periods and the ability to sustain high-frequency action potential discharge similar to that of dorsal column axons in control rats. Pharmacological results suggest that the myelin-deficient dorsal column axons qualitatively express a normal complement of ion channels and receptors. The demonstration of a normal representation of channels and receptors on these axons supports the proposal that the oligodendrocyte, and not the axon, is the site of the primary defect in the myelin-deficient rat mutant. It is concluded that, unlike acutely demyelinated axons which display marked frequency-dependent conduction block, amyelinated axons of the myelin-deficient rat spinal cord develop compensatory mechanisms to stabilize action potential conduction.

4-Aminopyridine↗
PubMed1996

Elemental composition and water content of rat optic nerve myelinated axons during in vitro post-anoxia reoxygenation.

During transient hypoxic episodes, CNS nerve cells and their axons undergo structural and functional damage. However, additional injury occurs as a result of subsequent tissue reperfusion. To examine mechanisms of this secondary injury, we have characterized the temporal patterns of element (e.g. Na, K, Ca) and water deregulation in rat optic nerve myelinated axons and glia during in vitro exposure to post-anoxia reoxygenation. Isolated nerves were exposed to 1 h of anoxia followed by varying periods of reoxygenation (20, 40, 60 and 180 min). Changes in subcellular distribution of elements and water were determined using electron probe X-ray microanalysis. In response to reoxygenation, the majority of large and medium axons exhibited a progressive worsening of anoxia-induced elemental deregulation. Axoplasmic Na, Cl and Ca increased substantially while K concentrations remained at or slightly below anoxic levels. Respective mitochondria expressed similar elemental changes except that Ca levels increased dramatically. A limited number of large and medium axons and their mitochondria showed initial but transient improvements in elemental composition. In contrast, approximately 50% of small axons initiated early improvements in transmembrane elemental distribution that continued to advance throughout the reoxygenation period. Remaining axons of this group displayed severe elemental derangement similar to that of larger fibers. The elemental composition of reoxygenated glial cells and myelin remained comparable to that reported after 60 min of anoxia. These results indicate that while larger axons express eventual severe elemental deregulation in spite of reoxygenation, many small axons appear capable of re-establishing near-normal transmembrane ion gradients. Results of the present study suggest reoxygenation/reperfusion injury of CNS axons is mediated by exacerbation of Ca2+ entry and the generalized ion deregulation initiated during anoxic or ischemic episodes. These findings constitute basic information regarding damage induced by post-anoxia reoxygenation and could, therefore, contribute toward understanding the mechanism of reperfusion injury following hypoxic or ischemic episodes in CNS white matter. Furthermore, deciphering the route of Ca2+ influx during reoxygenation/reperfusion might provide a basis for rational design of effective pharmacotherapies.

Animals↗
PubMed1982

Ultrastructural axonal pathology in experimentally diabetic and aging control rats.

Electron microscopic examination of tibial nerves from streptozotocin-diabetic, alloxan-diabetic and age-matched control rats was undertaken at two weeks and two, four, eight, and twelve months following the induction of diabetes. Many myelinated axons of both diabetic and control rats contained glycogen-like granules, axon-Schwann cell networks and fingerlike intrusions of myelin. These axonal changes were observed more frequently with advancing age and duration of diabetes, suggesting that they are related to aging or repeated injury. A larger proportion of diabetic axons than control axons were affected at early time periods, but by eight and twelve months the control axons were as frequently (or more frequently) involved as diabetic axons. Thus, experimental diabetes may confer upon peripheral myelinated axons an increased susceptability to aging or repeated injury. Specific morphologic abnormalities in peripheral myelinated axons associated uniquely with streptozotocin or alloxan diabetes in the rat were not noted.

Aging↗
PubMed1995

Crossed and uncrossed retinal axons respond differently to cells of the optic chiasm midline in vitro.

In mouse, retinal axon divergence takes place within a cellular specialization localized at the midline of the optic chiasm. To test whether the cells in this locus present cues for differential retinal axon growth, retinal explants were cocultured with cells dissociated from the chiasmatic midline, both taken from day 14-15 embryos, during the principal period of retinal axon divergence. Compared with crossed axons from other retinal regions, axons from ventrotemporal retina, the sole source of uncrossed axons, were shorter, more fasciculated, and fewer in number when growing on chiasm cells. Furthermore, uncrossed axons avoided clusters of chiasm neurons and glia having the composition and arrangement of the midline specialization, but crossed axons readily grew over them. In contrast to the clusters of chiasm cells, however, individual neurons and glia did not elicit differential retinal axon growth. These data demonstrate that cues for divergence derive from cells resident to the chiasm and suggest that cellular interactions among resident midline cells are required to produce these cues.

Animals↗
PubMed2006

MIG-10/lamellipodin and AGE-1/PI3K promote axon guidance and outgrowth in response to slit and netrin.

BACKGROUND: The cytoplasmic C. elegans protein MIG-10 affects cell migrations and is related to mammalian proteins that bind phospholipids and Ena/VASP actin regulators. In cultured cells, mammalian MIG-10 promotes lamellipodial growth and Ena/VASP proteins induce filopodia. RESULTS: We show here that during neuronal development, mig-10 and the C. elegans Ena/VASP homolog unc-34 cooperate to guide axons toward UNC-6 (netrin) and away from SLT-1 (Slit). The single mutants have relatively mild phenotypes, but mig-10; unc-34 double mutants arrest early in development with severe axon guidance defects. In axons that are guided toward ventral netrin, unc-34 is required for the formation of filopodia and mig-10 increases the number of filopodia. In unc-34 mutants, developing axons that lack filopodia are still guided to netrin through lamellipodial growth. In addition to its role in axon guidance, mig-10 stimulates netrin-dependent axon outgrowth in a process that requires the age-1 phosphoinositide-3 lipid kinase but not unc-34. CONCLUSIONS: mig-10 and unc-34 organize intracellular responses to both attractive and repulsive axon guidance cues. mig-10 and age-1 lipid signaling promote axon outgrowth; unc-34 and to a lesser extent mig-10 promote filopodia formation. Surprisingly, filopodia are largely dispensable for accurate axon guidance.

Animals↗
PubMed2004

Local neurotrophin effects on central trigeminal axon growth patterns.

In dissociated cell and wholemount explant cultures of the embryonic trigeminal pathway NGF promotes exuberant elongation of trigeminal ganglion (TG) axons, whereas NT-3 leads to precocious arborization [J. Comp. Neurol. 425 (2000) 202]. In the present study, we investigated the axonal effects of local applications of NGF and NT-3. We placed small sepharose beads loaded with either NGF or NT-3 along the lateral edge of the central trigeminal tract in TG-brainstem intact wholemount explant cultures prepared from embryonic day 15 rats. Labeling of the TG with carbocyanine dye, DiI, revealed that NGF induces local defasciculation and diversion of trigeminal axons. Numerous axons leave the tract, grow towards the bead and engulf it, while some axons grow away from the neurotrophin source. NT-3, on the other hand, induced localized interstitial branching and formation of neuritic tangles in the vicinity of the neurotrophin source. Double immunocytochemistry showed that axons responding to NGF were predominantly TrkA-positive, whereas both TrkA and TrkC-positive axons responded to NT-3. Our results indicate that localized neurotrophin sources along the routes of embryonic sensory axons in the central nervous system, far away from their parent cell bodies, can alter restricted axonal pathways and induce elongation, arborization responses.

Animals↗
PubMed2005

Age related optic nerve axonal loss in adult Brown Norway rats.

The effect of age on the number and morphology of optic nerve axons in adult Brown Norway rats (5-31 months old) (n=29) was examined using transmission electron microscopy (TEM). By manually counting every axon in areas representing 60% of the optic nerve cross-section, we found a significant negative correlation between age and axon count (R(2)=0.18, P<0.05). However, when the oldest animals were omitted, the relationship was no longer statistically significant. Simultaneously, the proportion of spontaneously degenerating axons increased at an exponential rate (R(2)=0.79, P<0.05), with significantly more degeneration in the 31-month group than in 5-month-old animals (ANOVA, P<0.05). This study demonstrates, using quantitative TEM methods, that optic nerve axonal numbers are relatively constant throughout the majority of the adult life of the Brown Norway rat, an increasingly popular strain for glaucoma research. Total axonal loss with aging is substantially less than that reported for other strains. The reduction in axonal numbers and the rate of axonal degeneration do not appear significantly altered until the last few months of life, failing to support some studies that have concluded that optic nerve axon loss in adult rats is linear. However, they do agree with other studies in the rat, and a similar study performed in non-human primate eyes, that concluded that aging changes in the optic nerve and retina follow a complex pattern. Therefore, the impact of animal age must be considered when modeling the course and pathophysiology of experimental glaucomatous optic nerve damage in rats.

Aging↗
PubMed2005

Lens epithelium supports axonal regeneration of retinal ganglion cells in a coculture model in vitro.

The purpose of this study was to determine whether the lens epithelium influences the survival or axonal growth of regenerating retinal ganglion cells. The optic nerves of adult albino rats were injured in order to induce axonal regeneration, and axon growth was then studied in retinal explants in the presence of cocultivated lens capsules carrying living epithelial cells. In the first series of experiments, cocultivation of retinal explants with lens epithelium in immediate proximity resulted in penetration of fibers into the lens epithelium, indicating that it supported axonal growth. In the second series of experiments, co-explants were placed 0.5-1.0mm from each other. The numbers of outgrowing retinal axons were determined both with respect to the retinal eccentricity and the topological relationship with the lenticular co-explant. The Wilcoxon matched-pairs signed-rank test was used to determine if the numbers of axons differed significantly between four regions of the explants. Significantly more axons grew out from the retinal edge facing the lenticular explant than from its opposite side, indicating that the lens epithelium supports axon growth. The numbers of surviving retinal ganglion cells in culture were determined after retrograde prelabelling with a neuroanatomical tracer. The number of fluorescent ganglion cells within the retinal explants did not significantly differ between the groups (Mann-Whitney test). These findings indicate that the lens epithelium influences both the amount of axonal regeneration and the direction of growth without affecting the survival rate of retinal ganglion cells in vitro.

Animals↗
PubMed2004

Myosin II activity is required for severing-induced axon retraction in vitro.

Understanding the mechanistic basis of the response of neurons to injury is directly relevant to the development of effective therapeutic approaches aimed at the amelioration of nervous system damage. Axons retract in response to severing. We investigated the mechanism of axon retraction in response to severing in vitro, testing the hypothesis that actomyosin contractility drives severing-induced axon retraction. Axon retraction commenced within 5 min following severing and correlated with actin filament accumulation at the site of severing. Depolymerization of actin filaments prevented retraction, demonstrating that actin filaments are required for severing-induced axon retraction. Direct inhibition of myosin II, using blebbistatin, minimized axon retraction in response to severing. Blocking RhoA-kinase (ROCK), a modulator of myosin II activity, inhibited axon retraction. Similarly, inhibiting myosin light chain kinase (MLCK) with a cell-permeable pseudo-substrate peptide also inhibited axon retraction. These data demonstrate that myosin II activity is required for severing-induced axon retraction in vitro, and suggest myosin II as a target for therapeutic interventions aimed at minimizing retraction following severing in vivo.

Actins↗
PubMed2005

BDNF-expressing marrow stromal cells support extensive axonal growth at sites of spinal cord injury.

Bone marrow stromal cells (MSCs) constitute a heterogeneous cell layer in the bone marrow, supporting the growth and differentiation of hematopoietic stem cells. Recently, it has been reported that MSCs harbor pluripotent stem cells capable of neural differentiation and that simple treatment of MSCs with chemical inducing agents leads to their rapid transdifferentiation into neural cells. We examined whether native or neurally induced MSCs would reconstitute an axonal growth-promoting milieu after cervical spinal cord injury (SCI), and whether such cells could act as vehicles of growth factor gene delivery to further augment axonal growth. One month after grafting to cystic sites of SCI, native MSCs supported modest growth of host sensory and motor axons. Cells "neurally" induced in vitro did not sustain a neural phenotype in vivo and supported host axonal growth to a degree equal to native MSCs. Transduction of MSCs to overexpress brain-derived neurotrophic factor (BDNF) resulted in a significant increase in the extent and diversity of host axonal growth, enhancing the growth of host serotonergic, coerulospinal, and dorsal column sensory axons. Measurement of neurotrophin production from implanted cells in the lesion site revealed that the grafts naturally contain nerve growth factor (NGF) and neurotrophin-3 (NT-3), and that transduction with BDNF markedly raises levels of BDNF production. Despite the extensive nature of host axonal penetration into the lesion site, functional recovery was not observed on a tape removal or rope-walking task. Thus, MSCs can support host axonal growth after spinal cord injury and are suitable cell types for ex vivo gene delivery. Combination therapy with other experimental approaches will likely be required to achieve axonal growth beyond the lesion site and functional recovery.

Animals↗
PubMed2005

Automated identification of axonal growth cones in time-lapse image sequences.

The isolation and purification of axon guidance molecules has enabled in vitro studies of the effects of axon guidance molecule gradients on numerous neuronal cell types. In a typical experiment, cultured neurons are exposed to a chemotactic gradient and their growth is recorded by manual identification of the axon tip position from two or more micrographs. Detailed and statistically valid quantification of axon growth requires evaluation of a large number of neurons at closely spaced time points (e.g. using a time-lapse microscopy setup). However, manual tracing becomes increasingly impractical for recording axon growth as the number of time points and/or neurons increases. We present a software tool that automatically identifies and records the axon tip position in each phase-contrast image of a time-lapse series with minimal user involvement. The software outputs several quantitative measures of axon growth, and allows users to develop custom measurements. For, example analysis of growth velocity for a dissociated E13 mouse cortical neuron revealed frequent extension and retraction events with an average growth velocity of 0.05 +/- 0.14 microm/min. Comparison of software-identified axon tip positions with manually identified axon tip positions shows that the software's performance is indistinguishable from that of skilled human users.

Animals↗
PubMed2006

Age increases axon loss associated with primary demyelination in cuprizone-induced demyelination in C57BL/6 mice.

Axon loss is recognised as a significant contributor to the progression of the disability associated with multiple sclerosis. Although evidence of axon damage is found in areas of chronic demyelination it is more frequently seen in association with acute demyelination. This study compares the incidence of axon degeneration associated with the areas undergoing demyelination in young adult (8-10 weeks) and aged (6-7 months) C57BL/6 mice in cuprizone intoxication; a widely used model of demyelination. The incidence of axon transection, as indicated by the presence of SMI 32 positive axonal spheroids, and evidence of axon loss in the medial corpus callosum, were significantly greater in aged mice, as was the magnitude of the macrophage and astrocyte response to demyelination. Aged C57BL/6 mice are thus more prone to axon degeneration in association with demyelination than young adult mice. A retrospective study indicated that the incidence of axon degeneration was much higher in C57BL/6 mice than in the Swiss albino mice used in the early cuprizone intoxication studies which were fed much higher doses of cuprizone. These results indicate both a genetic and age susceptibility to demyelination-associated axon transection.

Aging↗
PubMed2004

Theoretical consideration of olfactory axon projection with an activity-dependent neural network model.

Olfactory sensory neurons (OSNs) that express a given odorant receptor (OR) target their axons onto a few specific glomeruli in the olfactory bulb. Although the odorant receptor plays an indispensable role in olfactory axon targeting, the mechanisms underlying this guidance are largely unknown. In particular, there is much controversy regarding the involvement of activity-dependent mechanism in the targeting process. In this study, we developed an activity-dependent self-organization model of the glomerular layer in the olfactory bulb and simulated the targeting of olfactory axons onto the layer. Our model successfully constructed discrete glomeruli that received olfactory axons expressing a common odorant receptor through odorant-evoked neural activities. Furthermore, our model explained the perplexing experimental results that have been reported in olfactory axon targeting. For example, dispersion of olfactory axons in knockout mice for the odorant receptor gene was reasonably reproduced in the simulation. The segregated projection of the axons that express the same odorant receptor transcribed from the different alleles was also successfully simulated if the genetically modified allele was assumed to express a smaller amount of the receptor protein. The activity-dependent model even explained the inconsistent effects of disruption of the activity-evoking ion channel on axons expressing different odorant receptors, although some of these results were regarded as evidence for activity-independency of the olfactory targeting. Taken together, the activity-dependent targeting of olfactory axons seems to be a simple probable mechanism that can provide a unified explanation of glomerular formation.

Action Potentials↗
PubMed2004

Axonal responses to cellularly delivered NT-4/5 after spinal cord injury.

Neurotrophic factors delivered to the injured spinal cord have been shown to enhance axonal growth, prevent neuronal degeneration and partially improve sensorimotor function. The present study examined the effects of NT-4/5 on growth of spinal and supraspinal axons, glia, and functional outcome after spinal cord injury. Adult Fischer 344 rats received spinal cord dorsal hemisections or complete transections at the midthoracic level. Fibroblasts modified to secrete NT-4/5 or green fluorescent protein as controls were immediately grafted to the lesion site. Axonal growth responses were determined between 3 and 6 months postinjury by retrograde and anterograde tracing and immunohistochemistry. Motor axons, coerulospinal, reticulospinal, and propriospinal axons responded to NT-4/5 delivery after thoracic spinal cord injury with significantly increased axonal penetration into NT-4/5 secreting grafts compared to GFP-expressing control grafts. Axonal growth beyond NT-4/5-producing grafts and functional recovery were not observed. Numerous Schwann cells, but not oligodendrocytes, were present within NT-4/5-secreting grafts and remyelinated axons inside the graft. Thus, NT-4/5 and BDNF appear to be interchangeable to elicit substantial axonal growth in the injured spinal cord.

Animals↗
PubMed2004

Mutations affecting retinotectal axonal pathfinding in Medaka, Oryzias latipes.

We screened for mutations affecting retinotectal axonal projection in Medaka, Oryzias latipes. In wild-type Medaka embryos, all the axons of retinal ganglion cells (RGCs) project to the contralateral tectum, such that the topological relationship of the retinal field is maintained. We labeled RGC axons using DiI/DiO at the nasodorsal and temporoventral positions of the retina, and screened for mutations affecting the pattern of stereotypic projections to the tectum. By screening 184 mutagenized haploid genomes, seven mutations in five genes causing defects in axonal pathfinding were identified, whereas mutations affecting the topographic projection of RGC axons were not found. The mutants were grouped into two classes according to their phenotypes. In mutants of Class I, a subpopulation of the RGC axons branched out either immediately after leaving the eye or after reaching the midline, and this axonal subpopulation projected to the ipsilateral tectum. In mutants of Class II, subpopulations of RGC axons branched out after crossing the midline and projected aberrantly. These mutants will provide clues to understanding the functions of genes essential for axonal pathfinding, which may be conserved or partly divergent among vertebrates.

Animals↗
PubMed2004

Protein 4.1B localizes on unmyelinated axonal membranes in the mouse enteric nervous system.

Recent molecular studies on anchoring structures between myelin sheaths by glial cells (oligodendrocytes and Schwann cells (Sc) in the central (CNS) and peripheral nervous system (PNS), respectively) and axons indicated protein-protein interaction for the polarization of paranodes in the axons. The protein 4.1 (4.1) family was originally found in erythrocytes as a component of membrane skeletons, and genetic approaches revealed the precise family members. One of them, 4.1B, has been reported to be localized in paranodes and juxtaparanodes of myelinated axons. In this study, in addition to the myelinated axons, we also present the localization of 4.1B in nerve fibers in the adult mouse enteric nervous system, a subpopulation of mature unmyelinated nerve fibers in PNS. Ultrastructurally, 4.1B localized along the membranes of unmyelinated axons. Such unmyelinated axons were surrounded only by Sc, suggesting that the 4.1B may also have a role in direct Sc-axon interactions and maturation of the axons, as well as myelinating glial cell-axon interactions.

Animals↗
PubMed2006

Repulsive force based snake model to segment and track neuronal axons in 3D microscopy image stacks.

The branching patterns of axons and dendrites are fundamental structural properties that affect the synaptic connectivity of axons. Although today three-dimensional images of fluorescently labeled processes can be obtained to study axonal branching, there are no robust methods of tracing individual axons. This paper describes a repulsive force based snake model to segment and track axonal profiles in 3D images. This new method segments all the axonal profiles in a 2D image and then uses the results obtained from that image as prior information to help segment the adjacent 2D image. In this way, the segmentation successfully connects axonal profiles over hundreds of images in a 3D image stack. Individual axons can then be extracted based on the segmentation results. The utility and performance of the method are demonstrated using 3D axonal images obtained from transgenic mice that express fluorescent protein.

Algorithms↗
PubMed2005

Coordinated motor neuron axon growth and neuromuscular synaptogenesis are promoted by CPG15 in vivo.

We have used in vivo time-lapse two-photon imaging of single motor neuron axons labeled with GFP combined with labeling of presynaptic vesicle clusters and postsynaptic acetylcholine receptors in Xenopus laevis tadpoles to determine the dynamic rearrangement of individual axon branches and synaptogenesis during motor axon arbor development. Control GFP-labeled axons are highly dynamic during the period when axon arbors are elaborating. Axon branches emerge from sites of synaptic vesicle clusters. These data indicate that motor neuron axon elaboration and synaptogenesis are concurrent and iterative. We tested the role of Candidate Plasticity Gene 15 (CPG15, also known as Neuritin), an activity-regulated gene that is expressed in the developing motor neurons in this process. CPG15 expression enhances the development of motor neuron axon arbors by promoting neuromuscular synaptogenesis and by increasing the addition of new axon branches.

Animals↗