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PubMed1989

Regeneration of axons from the adult rat optic nerve: influence of fetal brain grafts, laminin, and artificial basement membrane.

After transection of the optic nerve of adult rats, most of the axons in the proximal stump die and the surviving ones are unable to regenerate into the distal optic nerve. Since the fetal brain has an inherent capacity to regenerate axons, we investigated whether fetal (E16) target regions of optic axons (thalamus and tectum) transplanted to the completely transected optic nerve of adult rats would promote axon regeneration. In control operated rats, axon growth beyond the site of transection was restricted to a few fibers that grew irregularly within the connective tissue scar. By contrast, in grafted animals directed outgrowth of optic axons toward the transplant started at 6 days postoperation (p.o.) and reached its maximum 15 days p.o. and later, when numerous single optic fibers and small axon fascicles had grown toward and into the graft, where they formed arborizations and terminal varicosities. Regenerating optic axons were further advanced than GFAP-positive strands of astroglia that emanated from the proximal optic nerve stump. Laminin immunoreactivity appeared at 6 days p.o. in the zone of reactive astroglia in the terminal part of the optic nerve stump. Later it showed a distribution complementary to the pattern of GFAP immunoreactivity, which it seemd to circumscribe. There was no unequivocal codistribution of laminin immunoreactivity with regenerating axons. In further experiments, target regions from different ontogenetic stages (E14 to neonate and adult) and nontarget regions (E16, cerebral cortex or spinal cord) were grafted to the optic nerve stump. With the exception of the adult grafts, all transplants had effects on axon regeneration comparable to those of E16 target regions. In order to test the effects of extracellular matrix molecules on axon regeneration, a basement membrane gel reconstituted from individual components of the Engelbreth-Holm-Sarcoma (EHS) sarcoma was implanted between proximal and distal optic nerve stumps. No axons were induced to regenerate by this matrix. Likewise, laminin adsorbed to nitrocellulose paper and implanted at the lesion site did not stimulate axon growth from the proximal optic nerve stump. These results indicate that fetal brain is able to induce and direct regrowth of axons from the optic nerve toward the graft across a substrate that is not composed of astroglia or basement membrane components like laminin. The directed growth of axons in the absence of a preformed substrate implies a chemotactic growth response along a concentration gradient mediated by neurotropic molecules released from the graft.

Animals↗
PubMed1990

Effect of temperature on long-term survival of anucleate giant axons in crayfish and goldfish.

The effect of temperature on the electrophysiology and morphology of anucleate axons was examined following severance of crayfish medial giant axons and goldfish Mauthner axons from their respective cell bodies. Although anucleate segments of each giant axon exhibited long-term survival for weeks to months at 5-25 degrees C in crayfish and 10-30 degrees C in goldfish, the two axons differed in their survival characteristics. All measures of long-term survival in crayfish medial giant axons were independent of animal holding temperature, whereas all measures in Mauthner axons were dependent on holding temperature. Medial giant axons survived for at least 90 days in crayfish maintained at 5-25 degrees C in this and previous studies. Mauthner axons survived for over 5 months in goldfish maintained at 10 degrees C but survived for 1 month at 30 degrees C. Postoperative time had different effects on many single measures of long-term survival (axonal diameter, amplitude of action or resting potentials) in medial giant axons compared to Mauthner axons. For example, resting and action potentials in crayfish medial giant axons remained remarkably constant at all holding temperatures for 0-90 postoperative days. In contrast, resting and action potentials in goldfish Mauthner axons declined abruptly in the first 10-20 postoperative days followed by a slower decline at each holding temperature. We suggest that the mechanism of long-term survival is not necessarily the same in all anucleate axons.

Animals↗
PubMed1991

Relationship of retinotopic ordering of axons in the optic pathway to the formation of visual maps in central targets.

We examined in rats the relationship between the ordering of retinal axons in the optic pathway and the formation of a retinotopically organized projection to their primary target, the contralateral superior colliculus (SC). We have previously found that axons labeled by focal injections of 1,1'-dioctadecyl 3,3,3',3'-tetramethylindocarbocyanine perchlorate (DiI) made in temporal or nasal retina of perinatal rats commonly mistarget along the medial-lateral and rostral-caudal axes of the SC. By postnatal day (P) 11-12, the retinocollicular projection attains an adult-like topography. Incorrectly targeted axons or axon segments are removed; axons that persist terminate in the topographically appropriate part of the SC (Simon and O'Leary: Dev Biol 137:125, 1990). In the present study, we made similar DiI injections, covering less than 2% of the retinal area, in peripheral temporal, nasal, superior, or inferior retina, in rats of two age groups, embryonic day (E) 21 to P (postnatal day) 2 and P11-P17. Whole mounts of retina, optic nerve and tract, and SC, and cross sections of the optic nerve, were examined. In E21-P2 rats, retinal axons labeled from each retinal site are diffusely distributed in the SC, and poorly ordered in the optic pathway. In retina, labeled axons travel in fascicles directly from the injection site to the optic disc, but neighbor relationships begin to degrade as fascicles split and mix. Retinotopic order is virtually lost in the optic nerve; axons labeled from each injection site disperse throughout its cross-sectional area, but the labeled axons tend to be concentrated toward a specific half of the nerve depending upon their retinal origin. This slight tendency toward retinotopic order increases in the optic tract, but axons are still poorly ordered as they leave the tract and enter the SC. Targeting errors along the medial-lateral axis of the SC, but apparently not along its rostral-caudal axis, are related to the positioning of axons across the width of the optic tract. In P11-P17 rats, axons labeled from each injection site arborize only in a small, topographically correct part of the SC. However, the distributions of labeled retinal axons observed in whole mounts of the retina and optic pathway have a degree of disorder similar to those in E21-P2 rats. Further, the scatter of labeled axons in optic nerve cross sections is comparable in both age groups. Therefore, the emergence of topographic order in the retinocollicular projection is not accompanied by an emergence of a retinotopic ordering of axons in the optic nerve.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗
PubMed1994

Axon overproduction and elimination in the anterior commissure of the developing rhesus monkey.

We have analyzed axon overproduction and elimination in the anterior commissure (AC) of 16 fetal, neonatal, and juvenile rhesus monkeys. Axons are added to the AC at an average rate of 115,000/day during the last two-thirds of gestation, and growth cones are present in a constant proportion to AC axons throughout this period. The peak number of approximately 11 million axons in the AC is reached at birth. Thereafter, axons are eliminated at a net rate of approximately 1 axon/sec during the first 3 postnatal months until the adult number of approximately 3.3 +/- 0.5 million axons is reached. Although there is considerable variability in AC axon number during the period of axon loss, the adult number of AC axons is relatively invariant among the eight adult rhesus monkeys examined. Increase in axon diameter and myelination begins before the major phase of axon elimination and is completed long after the adult number of axons is reached. Apparently, myelinated axons are not eliminated from the AC. Quantitative differences in the magnitude and timing of axon overproduction and elimination in the AC versus that in the corpus callosum (LaMantia and Rakic [1990] J. Neurosci. 10:2156) indicate specific modulation of the development of each commissure, perhaps reflecting differences in the developmental history and functional identity of the distinct cortical regions that give rise to them. This process of overproduction and elimination of AC axons during postnatal development in primates might contribute to individual variations in AC size correlated with a wide range of physical and behavioral differences.

Animals↗
PubMed1995

Chick wing innervation. II. Morphology of motor and sensory axons and their growth cones during early development.

The development and distribution of neuronal projections to the developing chick wing was studied using anterograde transport of horseradish peroxidase (HRP). Small injections of HRP were made into motor or sensory neuronal populations in order to visualize individual axons and their associated growth cones. Motor growth cones were observed in different regions of the embryo at different stages, in a proximal-to-distal pattern of distribution which paralleled the process of axon outgrowth and nerve formation. Different growth cone morphologies were associated with differing regions of the developing projection. In the spinal nerves, axons destined for the limb were unbranched and terminated in simply shaped growth cones. As axons approached the developing limb and entered the plexus region, their growth cones became more complex and larger primarily because of widening, and they sometimes branched, producing processes which could extend tens of microns from a tricorne branch point on the parent axon. Both motor and sensory fibers showed similar morphological changes in the plexus region. A distinctively shaped growth cone expanded on its leading edge was observed, sequentially apparent in the distal spinal nerves, in the plexus region, in the loosely organized axonal sheets projecting to the uncleaved dorsal or ventral muscle masses, and where muscle nerves diverged from nerve trunks and within muscle nerves. It is likely that some of these are transitional growth cones preparing to branch, because complex and branched growth cones were also observed in these regions. Branched axons oriented along the anteroposterior axis were similarly observed in the plexus region and distal to the plexus when axons first projected to the limb bud. At somewhat older stages when the basic peripheral nerve branching pattern had formed, motor growth cones were observed in common nerve trunks and in individual muscle nerves, but they were no longer found in the plexus region. Branched axons were likewise restricted to these peripheral locations. Taken together, these observations suggest that one of the ways in which axons navigate is by exploration in the form of growth cone widening, and in some cases terminal bifurcation which may produce axon branches. Selection of the most appropriately directed growth cone process and/or precocious axonal branches may be one of the ways in which axons respond to specific growth cues which guide axons into the limb bud. Alternatively, this precocious branching may be an early neurotrophic response to developing muscle and play no significant role in axon navigation.

Animals↗
PubMed1992

Axonal regeneration of an identified Helisoma neuron depends on the site of axotomy.

Axotomy of molluscan neurons usually results in axonal regeneration. In this study, we tested the axotomy response of an identified neuron of the pond snail Helisoma trivolvis (buccal neuron 4, B4). This neuron has two primary axonal branches, the ipsilateral axon and the contralateral axon, each innervating one of the paired salivary glands. The ipsilateral axon projects via the ipsilateral esophageal nerve trunk whereas the contralateral axon crosses both buccal ganglia and projects via the contralateral esophageal nerve trunk. We tested various procedures of axotomy: injury to one axon or both axons, close to the ganglion or more distal. Surprisingly, we found that proximal axotomy of the ipsilateral axon was not usually followed by axonal regeneration. By contrast, all other procedures of axotomy (e.g., distal ipsilateral, or proximal bilateral) resulted in robust axonal regeneration and target reinnervation. Thus, in this preparation, axotomy may or may not result in axonal regeneration, depending on the site(s) of axotomy. To the best of our knowledge, such a differential result has not yet been found in any other preparation. We conclude that axotomy is not always a sufficient condition for axonal regeneration of molluscan neurons. We hypothesize that a damaged axonal stump may be a necessary condition for the initiation of regeneration. An alternative hypothesis is that neurite outgrowth is inhibited in normal mature neurons by a target-derived factor. This hypothetical factor would be transported retrogradely, but not anterogradely, along axons.

Animals↗
PubMed1988

Study of axonal dystrophy. III. Posterior funiculus and posterior column of ageing and old rats.

Axonal dystrophy in normal ageing can be studied in experimental animals. Primary sensory neurones show two different kinds of change with ageing, i.e. axonal dystrophy and axonal atrophy (degeneration). This paper reports the chronology and topography of these two processes in relation to growth and involution of these neurones throughout the lifespan of the rats used in this study. Axonal spheroids preferentially form at presynaptic terminal regions in many of the collaterals of central branches of the axons, i.e. in the posterior funiculus nuclei, posterior column and posterior funiculus. Axonal dystrophy in normal ageing is essentially a morbid process restricted to the terminal parts of the axon. It shows little tendency to expand retrogradely along the axon. Evidence is presented that spheroids in posterior funiculus also derive from terminal axons. Preference is also noted in the lumbosacral rather than cervical neurons, and in longer (posterior funiculus nuclei) rather than shorter (posterior column) collaterals. Quantitative study of myelinated fibres in posterior funiculus shows that they increase in number until middle age (400 days) of the animals, before beginning to decline. On the other hand, axonal atrophy begins to appear early in small numbers, and increases in numbers with age. Atrophy involves the whole length of the axon within the posterior funiculus from the start, suggesting, therefore, that it does not belong to a dying-back process. It is noteworthy that the main development of axonal dystrophy lies in the earlier half of the animals' life, while that of axonal atrophy lies in the latter half. This fact adds to the evidence that axonal dystrophy, as far as in normal ageing is concerned, is more related to the positive side of neuronal activity, e.g. one form of growth abnormality of axon.

Aging↗
PubMed1994

Regrowth of axons in lesioned adult rat spinal cord: promotion by implants of cultured Schwann cells.

Highly purified populations of Schwann cells were grafted into lesioned adult rat spinal cord to determine if they promote axonal regeneration. Dorsal spinal cord lesions were created by a photochemical lesioning technique. Schwann cells derived from E16 rat dorsal root ganglia, either elongated and associated with their extracellular matrix or dissociated and without matrix, were rolled in polymerized collagen to form an implant 4-6 mm long which was grafted at 5 or 28 days after lesioning. No immunosuppression was used. Acellular collagen rolls served as controls. At 14, 28 and 90 days and 4 and 6 months after grafting, animals were analysed histologically with silver and Toluidine Blue stains and EM. The grafts often filled the lesion and the host borders they apposed exhibited only limited astrogliosis. By 14 days, bundles of unmyelinated and occasional thinly myelinated axons populated the periphery of Schwann cell implants. By 28 days and thereafter, numerous unmyelinated and myelinated axons were present in most grafts. Silver staining revealed sprouted axons at the implant border at 28 days and long bundles of axons within the implant at 90 days. Photographs of entire 1 micron plastic cross-sections of nine grafted areas were assembled into montages to count the number of myelinated axons at the graft midpoint; the number of myelinated axons ranged from 517-3214. Electron microscopy of implants showed typical Schwann cell ensheathment and myelination, increased myelin thickness by 90 days, and a preponderance of unmyelinated over myelinated axons. Random EM sampling of five Schwann cell grafts showed that the ratio of unmyelinated to myelinated axons was highest (20:1) at 28 days. These ratios implied that axons numbered in the thousands at the graft midpoint. Dissociated Schwann cells without matrix promoted axonal ingrowth and longitudinal orientation as effectively as did elongated Schwann cells accompanied by matrix. There was a suggestion that axonal ingrowth was at least as successful, if not more so, when the delay between lesioning and grafting was 28 rather than 5 days. Acellular collagen grafts did not contain axons at 28 days, the only interval assessed. In sum, grafts of Schwann cells in a rolled collagen layer filled the lesion and were well tolerated by the host. The Schwann cells stimulated rapid and abundant growth of axons into grafts and they ensheathed and myelinated these axons in the normal manner.

Animals↗
PubMed1996

Primary demyelination and regeneration of ascending axons in the dorsal funiculus of the rat spinal cord following photochemically induced injury.

The extent of primary demyelination and regeneration of ascending axons in the dorsal funiculus of the rat spinal cord was investigated following photochemically-induced ischaemic injury. Groups of rats were killed at intervals from 48h to 1 month after injury and a combination of light and electron microscopy and counting of axons in specific sites was used to study the axonal changes. Unmyelinated axons were noted in the dorsal rim of the lesion at its centre and at the centre of the gracile fasciculus at the caudal end of the lesion 7 days after injury. By 1 month, axons in these sites were thinly myelinated by Schwann cells or oligodendrocytes. In order to differentiate between remyelination of demyelinated axons and myelination of regenerated axons, axon counts were performed. The number of sub-pial axons present at the lesion centre did not change significantly from 48h to 1 month after injury, whereas the number of axons at the caudal end of the lesion increased significantly from 4 to 10 days after injury. We therefore conclude that sub-pial axons at the lesion centre are demyelinated between 4 and 7 days after injury and subsequently remyelinated by Schwann cells. At the caudal end of the lesion, a specific population of small diameter axons located at the centre of the gracile fasciculus regenerates for a distance of approximately 1 mm between 4 and 10 days after injury; these axons are then myelinated by oligodendrocytes or Schwann cells. In contrast, larger diameter axons of the gracile fasciculus do not show a regenerative response, demonstrating the variability of axonal responses to injury.

Animals↗
PubMed1999

Axonal degeneration with tympanal nerve of Schistocerca gregaria.

This study describes time course and ultrastructural changes during axonal degeneration of different neurones within the tympanal nerve of the locust Schistocerca gregaria. The tympanal nerve innervates the tergit and pleurit of the first abdominal segment and contains the axons of both sensory and motor neurones. The majority of axons (approx. 97%) belong to several types of sensory neurones: mechano- and chemosensitive hair sensilla, multipolar neurones, campaniform sensilla and sensory cells of a scolopidial organ, the auditory organ. Axons of campaniform sensilla, of auditory sensory cells and of motor neurones are wrapped by glial cell processes. In contrast, the very small and numerous axons (diameter <1 microm) of multipolar neurones and hair sensilla are not separated individually by glia sheets. Distal parts of sensory and motor axons show different reactions to axotomy: 1 week after separation from their somata, distal parts of motor axons are invaded by glial cell processes. This results in fascicles of small axon bundles. In contrast, distal parts of most sensory axons degenerate rapidly after being lesioned. The time to onset of degeneration depends on distance from the lesion site and on the type of sensory neurone. In axons of auditory sensory neurones, ultrastructural signs of degeneration can be found as soon as 2 days after lesion. After complete lysis of distal parts of axons, glial cell processes invade the space formerly occupied by sensory axons. The rapid degeneration of distal auditory axon parts allows it to be excluded that they provide a structure that leads regenerating axons to their targets. Proximal parts of severed axons do not degenerate.

Animals↗
PubMedDate not supplied

Role of axons in membrane phospholipid synthesis in rat sympathetic neurons.

The axonal synthesis of phospholipids has been demonstrated in compartmented cultures of rat sympathetic neurons. In this model of neuron culture, metabolic events occurring in distal axons were studied independently of those occurring in cell bodies. Using radiolabeled tracers the axonal biosynthesis of the major membrane phospholipids and fatty acids but not cholesterol was detected. The capacity of axons for synthesis of phosphatidylcholine (PC), the major membrane lipid, was confirmed by the demonstration that key enzymes of PC biosynthesis were present in distal axons. A double-labeling experiment showed that at least 50% of axonal PC was synthesized locally in axons, with the remainder being made in cell bodies and transported into axons. The requirement of axonal PC synthesis for axonal elongation was investigated. When PC biosynthesis in distal axons alone was inhibited by two independent approaches (deprivation of choline or addition of the inhibitor hexadecylphosphocholine) axonal growth was markedly retarded. Our experiments demonstrated that PC synthesis in cell bodies was neither necessary nor sufficient for growth of distal axons, whereas local synthesis of PC in distal axons was required for normal axonal elongation.

Animals↗
PubMed1983

Axonal physiology of chronic spinal cord injury in the cat: intracellular recording in vitro.

The properties of action potential conduction in single axons of the cat thoracic spinal cord were examined with microelectrode recording and electrical stimulation in vitro. The study included normal animals, animals chronically paralyzed by contusion of the cord, and animals showing some degree of locomotory recovery following a similar injury and several weeks of transient paralysis. The control studies were designed to compare the results of microelectrode sampling in vitro with morphological and in vivo physiological data. The pathophysiological studies were intended to investigate the continuity and function of axons identified morphologically in paralyzing lesions, and to examine the hypothesis that functional loss is associated with chronic axonal dysfunction, as well as direct axonal loss. Most of the recordings were made from dorsal columns and ventral tracts at 23-25 degrees C. The conduction velocities recorded in the normal cord were consistent with morphological data on caliber spectra, given the selectivity of the microelectrodes for larger axons. The refractory period of transmission was approximately 2-4 ms at 23-25 degrees C and 0.7-2 ms at 37 degrees C. Prolonged depolarizing after-potentials were recorded, following action potentials greater than 70 mV amplitude. Axons outside the lesion in injured cord showed only slight reductions from control in the mean and range of conduction velocity and refractory period distributions. The number of axons impaled per electrode track was reduced by up to one half. Relatively few impaled axons conducted through the lesion site in the injured cords: 16% in recovering animals and 7% in chronically paralyzed, as compared with 61% in uninjured controls. The mean conduction velocity of these through-conducting axons was significantly less than that of the normal population, particularly in paralyzed animals, and refractory period was significantly prolonged for conduction through the lesion in the paralyzed group. When axons conducting through the middle of the isolated spinal tract were challenged by raising the temperature, conduction block occurred below physiological temperature (37 degrees C) for 7% of axons in controls, 14% in recovering and 73% in paralyzed cats. The mean temperature of heat block in normal axons was 41 degrees C. Some axons appear to survive in paralyzing contusion trauma of this type. Those axons that remain in the lesion site project through it but their conduction properties are abnormal, particularly in animals that remain chronically paralyzed. Action potentials in many axons may be effectively blocked at the chronic lesion site, contributing to the overall functional d

Animals↗
PubMed1991

Anatomical correlations between soma size, axon diameter, and intraretinal length for the alpha ganglion cells of the cat retina.

Retinal ganglion cells within the same region of the retina may have different lengths of axon before reaching the optic disc depending on the route they take with respect to the temporal raphe. We have investigated whether there is a correlation between soma and intraretinal axon diameter and how these parameters relate to intraretinal axon length on both sides of the cat temporal raphe. Retinas were wholemounted and alpha-cell somata and fibers stained with a modified neurofibrillar method. Moving peripherally from the area centralis along the raphe there was a progressively increasing difference between the intraretinal axon lengths for nearly adjacent cells across the raphe, which reached a maximum of 4-5 mm at the retinal periphery. Cells on the nasal aspect of the raphe had shorter axons than did adjacent cells on the temporal aspect of the raphe. Comparison of soma diameter samples across the raphe showed there was no clear trend between soma diameter and intraretinal length. Replotting the raphe and sample areas on a cell density map indicated that differences in soma diameter could be attributed to ganglion-cell density differences between the sampled areas. Examination of the stained cells revealed that within the initial length of the axon there was a region showing a reduction of axon diameter (diameter less than 1 micron), which varied in length from cell to cell. The axon was, therefore, divided into three segments: the portion of axon prior to thinning (A), the thin segment itself (B), and the part of the axon after the thin segment (C). The diameter of each segment (A,B,C) and the lengths of the first and second segments (A,B) were significantly correlated with soma diameter (P less than 0.001). From measurements of the axon diameter of segment C, it was concluded that alpha-cell axons continue to increase in diameter along their path towards the optic disc. The present report indicates that alpha-cell soma size, when going from the area centralis to the periphery along the raphe, reaches a plateau and then declines within more peripheral retinal locations in spite of increasing intraretinal axon length. Thus, there is no positive correlation between soma or axon diameter and intraretinal axon length. The anatomical findings are discussed in relation to previous reports of retinal development and complementary conduction times within intraretinal and extraretinal visual pathways.

Animals↗
PubMed1993

The transport properties of axonal microtubules establish their polarity orientation.

It is well established that axonal microtubules (MTs) are uniformly oriented with their plus ends distal to the neuronal cell body (Heidemann, S. R., J. M. Landers, and M. A. Hamborg. 1981. J. Cell Biol. 91:661-665). However, the mechanisms by which these MTs achieve their uniform polarity orientation are unknown. Current models for axon growth differ with regard to the contributions of MT assembly and transport to the organization and elaboration of the axonal MT array. Do the transport properties or assembly properties of axonal MTs determine their polarity orientation? To distinguish between these possibilities, we wished to study the initiation and outgrowth of axons under conditions that would arrest MT assembly while maintaining substantial levels of preexisting polymer in the cell body that could still be transported into the axon. We found that we could accomplish this by culturing rat sympathetic neurons in the presence of nanomolar levels of vinblastine. In concentrations of the drug up to and including 100 nM, the neurons actively extend axons. The vinblastine-axons are shorter than control axons, but clearly contain MTs. To quantify the effects of the drug on MT mass, we compared the levels of polymer throughout the cell bodies and axons of neurons cultured overnight in the presence of 0, 16, and 50 nM vinblastine with the levels of MT polymer in freshly plated neurons before axon outgrowth. Without drug, the total levels of polymer increase by roughly twofold. At 16 nM vinblastine, the levels of polymer are roughly equal to the levels in freshly plated neurons, while at 50 nM, the levels of polymer are reduced by about half this amount. Thus, 16 nM vinblastine acts as a "kinetic stabilizer" of MTs, while 50 nM results in some net MT disassembly. At both drug concentrations, there is a progressive increase in the levels of MT polymer in the axons as they grow, and a corresponding depletion of polymer from the cell body. These results indicate that highly efficient mechanisms exist in the neuron to transport preassembled MTs from the cell body into the axon. These mechanisms are active even at the expense of the cell body, and even under conditions that promote some MT disassembly in the neuron. MT polarity analyses indicate that the MTs within the vinblastine-axons, like those in control axons, are uniformly plus-end-distal.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗
PubMed1997

Quantitative analysis of acute axonal pathology in experimental spinal cord contusion.

The major sensorimotor deficits that result from traumatic spinal cord injury (SCI) are due to loss of axons in ascending and descending pathways of the white matter (WM). Experimental treatments administered after a standardized SCI can reduce WM loss and long-term functional deficits. Thus, a significant proportion of WM loss occurs secondary to the mechanical injury and may be a target for therapeutic intervention. Presently, we know little of how and when secondary injury mechanisms operate in the WM after SCI. We therefore used a standardized rat model of clinically relevant contusion injury to examine axonal pathology over the first 24 h by light and electron microscopy. Based on qualitative evaluation of tissue at 15 min, 4 h, and 24 h after a "mild" SCI produced with a weight-drop device (10 g x 2.5 cm), we selected areas from the ventromedial WM at the lesion epicenter for quantitative analyses. We compared axon number and the proportion of axons with various axoplasmic and myelin abnormalities over time after SCI, as well as the effect of axon size on degree of pathology and loss. We found by 4 h postinjury (pi) axonal pathology was more severe than at 15 min and that a significant loss of large diameter axons had occurred; no significant additional loss of axons was seen by 24 h pi. When we compared axonal pathology after a more severe contusion (10 g x 17.5 cm), we found a greater loss of axons at 4 h. In addition, a higher proportion of the remaining axons demonstrated pathological alterations. We developed a semi-quantitative Axonal Injury Index (AII) as an overall measure of axonal pathology that was sensitive to the effects of injury severity at 4 h pi. The AII has greater statistical power than our individual measures of axonal pathology. Our results suggest that it may be possible to use the AII at 4 h pi to assess effects of potential therapeutic agents on acute axonal pathology after SCI.

Animals↗
PubMed2003

Demyelinating and axonal features of Charcot-Marie-Tooth disease with mutations of myelin-related proteins (PMP22, MPZ and Cx32): a clinicopathological study of 205 Japanese patients.

Three genes commonly causing Charcot-Marie-Tooth disease (CMT) encode myelin-related proteins: peripheral myelin protein 22 (PMP22), myelin protein zero (MPZ) and connexin 32 (Cx32). Demyelinating versus axonal phenotypes are major issues in CMT associated with mutations of these genes. We electrophysiologically, pathologically and genetically evaluated demyelinating and axonal features of 205 Japanese patients with PMP22 duplication, MPZ mutations or Cx32 mutations. PMP22 duplication caused mainly demyelinating phenotypes with slowed motor nerve conduction velocity (MCV) and demyelinating histopathology, while axonal features were variably present. Two distinctive phenotypic subgroups were present in patients with MPZ mutations: one showed preserved MCV and exclusively axonal pathological features, while the other was exclusively demyelinating. These axonal and demyelinating phenotypes were well concordant among siblings in individual families, and MPZ mutations did not overlap among these two subgroups, suggesting that the nature and position of the MPZ mutations mainly determine the axonal and demyelinating phenotypes. Patients with Cx32 mutations showed intermediate slowing of MCV, predominantly axonal features and relatively mild demyelinating pathology. These axonal and demyelinating features were present concomitantly in individual patients to a variable extent. The relative severity of axonal and demyelinating features was not associated with particular Cx32 mutations. Median nerve MCV and overall histopathological phenotype changed little with disease advancement. Axonal features of diminished amplitudes of compound muscle action potentials (CMAPs), axonal loss, axonal sprouting and neuropathic muscle wasting all changed as disease advanced, especially in PMP22 duplication and Cx32 mutations. Median nerve MCVs were well maintained independently of age, disease duration and the severity of clinical and pathological abnormalities, confirming that median nerve MCV is an excellent marker for the genetically determined neuropathic phenotypes. Amplitude of CMAPs was correlated significantly with distal muscle strength in PMP22 duplication, MPZ mutations and Cx32 mutations, while MCV slowing was not, indicating that clinical weakness results from reduced numbers of functional large axons, not from demyelination. Thus, the three major myelin-related protein mutations induced varied degrees of axonal and demyelinating phenotypic features according to the specific gene mutation as well as the stage of disease advancement, while clinically evident muscle wasting was attributable to loss of functioning large axons.

Action Potentials↗
PubMed2003

Co-localization of sodium channel Nav1.6 and the sodium-calcium exchanger at sites of axonal injury in the spinal cord in EAE.

Axonal degeneration contributes to the development of non-remitting neurological deficits and disability in multiple sclerosis, but the molecular mechanisms that underlie axonal loss in multiple sclerosis are not clearly understood. Studies of white matter axonal injury have demonstrated that voltage-gated sodium channels can provide a route for sodium influx into axons that triggers reverse operation of the Na(+)/Ca(2+) exchanger (NCX) and subsequent influx of damaging levels of intra-axonal calcium. The molecular identities of the involved sodium channels have, however, not been determined. We have previously demonstrated extensive regions of diffuse expression of Na(v)1.6 and Na(v)1.2 sodium channels along demyelinated axons in experimental allergic encephalomyelitis (EAE). Based on the hypothesis that the co-localization of Na(v)1.6 and NCX along extensive regions of demyelinated axons may predispose these axons to injury, we examined the expression of myelin basic protein, Na(v)1.2, Na(v)1.6, NCX and beta-amyloid precursor protein (beta-APP), a marker of axonal injury, in the spinal cord dorsal columns of mice with EAE. We demonstrate a significant increase in the number of demyelinated axons demonstrating diffuse Na(v)1.6 and Na(v)1.2 sodium channel immunoreactivity in EAE (92.2 +/- 2.1% of beta-APP positive axons were Na(v)1.6-positive). Only 38.0 +/- 2.9% of beta-APP positive axons were Na(v)1.2 positive, and 95% of these co-expressed Na(v)1.6 together with Na(v)1.2. Using triple-labelled fluorescent immunohistochemistry, we demonstrate that 73.5 +/- 4.3% of beta-APP positive axons co-express Na(v)1.6 and NCX, compared with 4.4 +/- 1.0% in beta-APP negative axons. Our results indicate that co-expression of Na(v)1.6 and NCX is associated with axonal injury in the spinal cord in EAE.

Amyloid beta-Protein Precursor↗
PubMedDate not supplied

Transitory corpus callosum axons projecting throughout developing rat visual cortex revealed by Dil.

Anatomical tracing was used to determine the extent and distribution of CC axons in mammalian visual cortex. Postnatal development of rat CC was studied by in vitro callosal labeling with the lipophilic carbocyanine dye Dil in 59 rats. Solid Dil crystals were placed in the mid-sagittal region of the CC in aldehyde-fixed brain slabs. Coronal sections through visual cortex were photographed and reconstructed to show the overall distribution of Dil-labeled callosal projections as well as the locations of individual callosal axons and their presumed synaptic boutons. During postnatal weeks 1 and 2, CC axons were found to project to layer I throughout the entire mediolateral extent of areas 17, 18a, and 18b. Numerous varicosities on callosal axons are located en passant and at axon terminals in layer I. During postnatal week 3 the tangential density of callosal projections was significantly reduced, so that fewer callosal axons extended to layer I throughout areas 17, 18a, and 18b than in younger postnatal rats. However, at this age some CC axons could still be found extending to layer I throughout the mediolateral extent of areas 17, 18a, and 18b. By postnatal week 4 the tangential distribution of callosal projections was greatly restricted; most callosal axons projecting to layer I were located at the borders of the visual cortical areas. Nevertheless, there were still callosal axons projecting into cortex and terminating in supragranular and infragranular layers in areas 17, 18a, and 18b; this was most pronounced in area 18a. Thus, in the rat there are many elaborately formed transitory CC axons projecting throughout visual cortex for several weeks postnatal. These projections extend to layer I and have varicosities in all cortical layers. With increasing age, fewer axons extended to layer I; subsequently most axons not at cytoarchitectonic borders fail to extend to layer I. If some of the varicosities on the transitory rat callosal axons were to form synapses, there would be extensive opportunities for the CC to provide input to all layers of visual cortical areas while cortical microcircuitry is being established. The same type of study in the cat has shown similar results during early postnatal development. Cat CC axons project to all parts of primary and association visual cortical areas; even in regions found to be acallosal in the adult, the neonatal callosal axons extend through all layers of cortex to reach layer I (Elberger, 1993).(ABSTRACT TRUNCATED AT 400 WORDS)

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