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PubMed1988

Methylenedioxyamphetamine (MDA) and methylenedioxymethamphetamine (MDMA) cause selective ablation of serotonergic axon terminals in forebrain: immunocytochemical evidence for neurotoxicity.

The psychotropic amphetamine derivatives 3,4-methylenedioxyamphetamine (MDA) and 3,4-methylenedioxymethamphetamine (MDMA) have been used for recreational and therapeutic purposes in man. In rats, these drugs cause large reductions in brain levels of serotonin (5-HT). This study employs immunocytochemistry to characterize the neurotoxic effects of these compounds upon monoaminergic neurons in the rat brain. Two weeks after systemic administration of MDA or MDMA (20 mg/kg, s.c., twice daily for 4 d), there is profound loss of serotonergic (5-HT) axons throughout the forebrain; catecholamine axons are completely spared. Regional differences in drug toxicity are exemplified by partial sparing of 5-HT axons in hippocampus, lateral hypothalamus, basal forebrain, and in some areas of neocortex. The terminals of 5-HT axons are selectively ablated, while axons of passage and raphe cell bodies are spared. Thickened preterminal fibers exhibit increased staining due to damming-up of neurotransmitter and other axonal constituents. Fine 5-HT axon terminals are extremely vulnerable to these drugs, whereas terminal-like axons with large varicosities survive, raising the possibility that some 5-HT axons may be resistant to the neurotoxic effects. At short survivals, visualization of greatly swollen, fragmented 5-HT axons provides anatomic evidence for degeneration of 5-HT projections. The results establish that MDA and MDMA produce structural damage to 5-HT axon terminals followed by lasting denervation of the forebrain. Both drugs have similar effects, but MDA produces a greater reduction of 5-HT axons than does MDMA at the same dosage. The selective degeneration of 5-HT axons indicates that these drugs may serve as experimental tools to analyze the organization and function of 5-HT projections. Caution should be exercised until further studies determine whether these compounds may be hazardous in man.

3,4-Methylenedioxyamphetamine↗
PubMed1981

Development of a sensory afferent projection in the grasshopper embryo. II. Growth and branching of peripheral sensory axons within the central nervous system.

The morphogenesis of several types of sensory axon branching patterns has been described by cobalt filling the cercal nerve of the grasshopper embryo at a series of different stages in development, thus staining the earliest sensory axons as they grow through the CNS. This embryonic sensory projection contains all five types of cercal afferents seen in the adult, and no new sensory tracts are added during postembryonic life. When the embryonic sensory axons first follow their pioneer axons into the neuropil they choose pathways which are characteristic of the adult sensory tracts. Since the afferents follow these paths without sending collaterals into the other tracts, it appears that the growth axon chooses its specific pathway without extensive exploration of alternative routes. Likewise, nearly all of the branches which arise from the embryonic sensory axons remain within the eventual domain characteristic of each cell type. This precise, determinate pattern of initial growth implies that the sensory axons are guided through the neuropil and achieve their final branching patterns with a minimum of overgrowth and pruning. The fact that initial growth is so precise also suggests that the parameters which guide the growing axon may help to determine its eventual pattern of synaptic connectivity by limiting its physical access to large portions of the neuropil which contain potentially compatible synaptic partner cells. Two different types of neurons may be supplying the sensory afferents with guidance cues: (i) Although most of the cercal sensory axons diverge from the cercal pioneer axons within the CNS, some sensory afferents continue to follow the pioneers through several ganglia. (ii) In the adult, a large number of the cercal sensory axons form a hollow shell of arborization around the main dendrite of an identified synaptic target cell, the Medical Giant Interneuron (MGI). This structure, the interneuron dendrite and the shell of sensory arbor, is called the cercal glomerulus. Since the MGI's dendrite is already present at the stage when the first sensory axons enter the CNS, interactions between these cells could serve to guide the glomerular sensory axons away from the pioneers into their future tracts.

Animals↗
PubMed1981

Demyelination in experimental beta, beta'-iminodipropionitrile and hexacarbon neuropathies. Evidence for an axonal influence.

beta, beta'-Iminodipropionitrile and 2,5-hexanediol are best known for their ability to induce axonal pathology, including formation of giant axonal swellings. During studies of the pathology of rats exposed to these agents for long periods, we found extensive recurrent demyelination in the spinal roots. To determine whether the demyelination occurred in response to the axonal disease or whether it represented a direct toxic effect on Schwann cells, we examined the time course and distribution of axonal changes and demyelination, asking whether demyelination correlated with, or was independent of, axonal pathology. Experimental animals were continuously intoxicated with one of these agents, and groups were taken for pathologic examination at intervals of up to 2 years; in both models, the relationship between axonal pathology and demyelination was systematically studied in multiple regions of the L5 spinal roots. In control rats, mild demyelination was present by 14 months and increased with age. By 24 months, untreated animals showed widespread demyelination in the spinal roots; in these animals, there was no predilection for proximal or distal regions of the roots, nor was their evidence of recurrent demyelination. Administration of beta, beta'-iminodipropionitrile produced giant axonal swellings located primarily in the proximal 10 mm. of the ventral root and the distal 10 mm. of the dorsal root. By 12 months of exposure, intramyelinic vacuoles (myelin bubbles) and demyelinated segments were numerous in the same regions. By 24 months, the affected regions contained elaborate onion bulbs. The regions without axonal swellings showed only mild demyelination. In contrast, in the 2,5-hexanediol group, giant axonal swellings and axonal degeneration began distally and progressed more proximally with time. By 15 months, when axonal swellings were present primarily in the distal ventral root, there were numerous myelin bubbles. By 24 months, onion bulbs, predominantly involving the distal ventral roots, had developed. Semiquantitative analysis of the time course and distribution of demyelination in these toxic models showed a relationship between axonal abnormalities and subsequent development of demyelination. We concluded that changes in the axons contribute to the development of demyelination in these models and determine the distribution of the lesions. These experimental neuropathies provide models for studies of the stimulus and mechanisms of secondary demyelination.

Animals↗
PubMed1995

Sensory neurons selectively upregulate synthesis and transport of the beta III-tubulin protein during axonal regeneration.

The effects of peripheral nerve injury on the content, synthesis, and axonal transport of the class III beta-tubulin protein in adult rat dorsal root ganglion (DRG) neurons were examined. Recent reports of selective increases in the steady-state levels of the beta III-tubulin mRNA during axonal regeneration (Moskowitz et al., 1993) led to the hypothesis that upregulated levels of expression of the beta III-tubulin isotype that alter the composition of neuronal microtubules is important for effective axonal regrowth. If this is the case, the increases in mRNA levels must be translated into increased beta III-tubulin protein levels and subsequently modify the axonal cytoskeleton via axonal transport mechanisms. The present study assessed whether or not this occurs by examining beta III-tubulin protein content in adult rat lumbar DRG neurons at different times (1-14 d) after a distal sciatic nerve crush (approximately 55 mm from the DRG) by Western blotting and immunocytochemistry with a beta III-tubulin specific monoclonal antibody. These studies showed substantial increases in beta III-tubulin content in DRG neurons, as well as in proximal regions of peripheral sensory axons (0-6 mm from the DRG), from 1-2 weeks after a distal nerve injury. Pulse labeling of DRG neurons with 35S-methionine and 35S-cysteine and immunoprecipitation of labeled beta III-tubulin indicated that the synthesis of beta III-tubulin was increased in the DRG after axotomy. Studies of axonal transport, wherein L5 DRG proteins were labeled with 35S-methionine and 35S-cysteine by microinjection, revealed that slow component b(SCb) of axonal transport conveyed more labeled tubulin moving at apparently faster rates through the intact regions of sciatic nerve axons in response to crush injury of the distal sciatic nerve. Immunoprecipitation experiments using proximal peripheral nerve segments showed that SCb in distally injured DRG neurons was enriched in the beta III-tubulin isotype. These findings demonstrate that the augmented synthesis of beta III-tubulin after axotomy alters the composition of the axonally transported cytoskeleton that moves with SCb. The increased amounts and rate of delivery of beta III-tubulin in axons of regenerating DRG neurons suggest that the altered pattern of tubulin gene expression that is initiated by axotomy impacts on the composition and organization of the axonal cytoskeleton in a manner that can facilitate axonal regrowth.

Animals↗
PubMed1996

Tau is enriched on dynamic microtubules in the distal region of growing axons.

It is widely held that tau determines the stability of microtubules in growing axons, although direct evidence supporting this hypothesis is lacking. Previous studies have shown that the microtubule polymer in the distal axon and growth cone is the most dynamic of growing axons; it turns over more rapidly and is more sensitive to microtubule depolymerizing drugs than the polymer situated proximally. We reasoned that if the stability of axonal microtubules is directly related to their content of tau, then the polymer in the distal axon should have less tau than the polymer in the proximal axon. We tested this proposition by measuring the relative tau content of microtubule along growing axons of cultured sympathetic neurons immunostained for tau and tubulin. Our results show that the tau content of microtubules varies along the axon, but in the opposite way predicted. Specifically, the relative tau content of microtubules increases progressively along the axon to reach a peak near the growth cone that is severalfold greater than that observed proximally. Thus, tau is most enriched on the most dynamic polymer of the axon. We also show that the gradient in tau content of microtubules does not generate corresponding gradients in the extent of tubulin assembly or in the sensitivity of axonal microtubules to nocodazole. On the basis of these findings, we propose that tau in growing axons has functions other than promoting microtubule assembly and stability and the key sites for these functions are the distal axon and growth cone.

Adrenergic Fibers↗
PubMed1998

Activity-dependent development of calcium regulation in growing motor axons.

In cultured nerve cord explants from the crayfish (Procambarus clarkii), the normal impulse activity levels of growing motor axons determine their response to Ca2+ influx. During depolarization or Ca2+ ionophore application, normally active tonic motor axons continue to grow, whereas inactive phasic motor axons retract and often degenerate. To determine the role of Ca2+ regulation in this difference, we measured the intracellular free Ca2+ concentration ([Ca2+]i) with fura-2. Growth cones from tonic axons normally had a higher [Ca2+]i than those from phasic axons. When depolarized with 60 mM K+, growth cones and neurites from phasic axons had a [Ca2+]i three to four times higher than did those from tonic axons. This difference in Ca2+ regulation includes greater Ca2+-handling capacity for growing tonic axons; the increase in [Ca2+]i produced by the Ca2+ ionophore 4-bromo-A23187 (0.25 microM) is four to five times greater in phasic than in tonic axons, and the decline in [Ca2+]i at the end of a depolarizing pulse is three to four times faster in tonic axons than phasic ones. Blocking impulses in growing tonic axons for 2-3 d with tetrodotoxin reduces their capacity to regulate [Ca2+]i. Thus, growing tonic and phasic axons have differences in Ca2+ regulation that develop as a result of their different activity levels. These activity-dependent differences in Ca2+ regulation influence axon growth and degeneration and probably influence other neuronal processes that are mediated by changes in [Ca2+]i.

Animals↗
PubMed1998

Retinal ganglion cell axon progression from the optic chiasm to initiate optic tract development requires cell autonomous function of GAP-43.

Pathfinding mechanisms underlying retinal ganglion cell (RGC) axon growth from the optic chiasm into the optic tract are unknown. Previous work has shown that mouse embryos deficient in GAP-43 have an enlarged optic chiasm within which RGC axons were reportedly stalled. Here we have found that the enlarged chiasm of GAP-43 null mouse embryos appears subsequent to a failure of the earliest RGC axons to progress laterally through the chiasm-tract transition zone to form the optic tract. Previous work has shown that ventral diencephalon CD44/stage-specific embryonic antigen (SSEA) neurons provide guidance information for RGC axons during chiasm formation. Here we found that in the chiasm-tract transition zone, axons of CD44/SSEA neurons precede RGC axons into the lateral diencephalic wall and like RGC axons also express GAP-43. However unlike RGC axons, CD44/SSEA axon trajectories are unaffected in GAP-43 null embryos, indicating that GAP-43-dependent guidance at this site is RGC axon specific or occurs only at specific developmental times. To determine whether the phenotype results from loss of GAP-43 in RGCs or in diencephalon components such as CD44/SSEA axons, wild-type, heterozygous, or homozygous GAP-43 null donor retinal tissues were grafted onto host diencephalons of all three genotypes, and graft axon growth into the optic tract region was assessed. Results show that optic tract development requires cell autonomous GAP-43 function in RGC axons and not in cellular elements of the ventral diencephalon or transition zone.

Animals↗
PubMed2004

The developing cervical spinal ventral commissure of the rat: a highly controlled axon-glial system.

The floor plate of the neural tube is of major importance in determining axonal behaviour, such that, having crossed, decussating axons do not cross back again. The ventral commissure (VC) of the spinal cord forms immediately ventral to the floor plate shortly after neural tube closure. It is the principal location in which decussating axons cross the midline. It is probably also of major importance in neural tube development, but has received relatively little attention. This study analyses the growth and development of the rat VC and also axon-glial relationships within it throughout the crucial prenatal period of extensive transmedian axon growth, when key biochemical interactions between the two tissues are taking place. The morphometric, stereological and immunohistochemical methods used show that the axonal and glial populations remain in a finely balanced equilibrium throughout a period of almost a hundred-fold growth of both elements. At all stages axons are highly segregated into small bundles of constant size by glial processes, to which they are closely apposed. Thus, glial-axon contact is remarkably precocious, uniquely intimate and persists throughout VC development. This suggests that the relationship between the two tissues is highly controlled through interactions between them. The VC is likely to be the physical basis of a second set of glial-axonal interactions, namely, those which are well known to influence axon crossing behaviour. In mediating these, the extensive axon-glial contact is an ideal arrangement for molecular transfer between them, and is probably the substrate for altering axon responsiveness and ensuring reliable transmedian decussation. The VC is therefore a segregating matrix temporally and spatially specialised for a range of key developmental axon-glial interactions.

Animals↗
PubMed1984

The neuronal endoplasmic reticulum: its cytochemistry and contribution to the endomembrane system. II. Axons and terminals.

The morphology and cytochemistry of the endoplasmic reticulum (ER) in axons and terminals of a number of different types of neurons in brains from mice were investigated ultrastructurally. The neurohypophysis received particular attention because the morphology and enzyme cytochemical activities of many of the preterminal swellings of hypothalamo-neurohypophysial axons are altered by chronic salt-stress. Membrane contrast and enzyme cytochemical staining techniques were employed to characterize the axonal reticulum and to determine if organelles representing the lysosomal system in the axon and the tubular profiles participating in the anterograde axonal transport of native horseradish peroxidase (HRP) are associated with the ER. Potential enzyme cytochemical markers for the axonal ER included glucose-6-phosphatase (G6Pase), thiamine pyrophosphatase, nucleoside diphosphatase, and acid hydroxylase activities. The anterograde transport of HRP was analyzed in undamaged hypothalamo-neurohypophysial neurons and in facial and hypoglossal motoneurons of mice receiving the protein in the lateral cerebral ventricle. The ER pervaded the axon and appeared as parallel, 20-40-nm-wide tubules interconnected by oblique anastomoses. Membrane thickness of the axonal reticulum measured 60-100 A, which is similar to that of the perikaryal ER. Enzyme cytochemical activities associated with the ER or lysosomes were not conspicuous in axons and terminals under normal conditions but became prominent in some axons and preterminal swellings manifesting an autophagic appearance within neurohypophyses from salt-stressed mice. Only G6Pase activity was a marker for the ER in these axons and preterminals. Many ER profiles in non-incubated sections and in G6Pase cytochemical preparations of salt-stressed neurohypophyses were wrapped around or interspersed among secretory granules, multilamellar bodies, and vacuoles that may represent forms of lysosomes involved in autophagy and crinophagy. Acid hydrolase activities were localized within the vacuoles as well as within 80-130-nm-wide, blunt-ended tubules in pituitary stalk axons; similar reactive tubules were confluent with large secondary lysosomes in neurosecretory cell bodies and may be derived from these lysosomes. Morphologically identical tubules transporting HRP in the anterograde direction were observed only in the salt-stressed hypothalamo-neurohypophysial neuron. The HRP-positive tubules very likely are affiliated with the lysosomal system.

Acid Anhydride Hydrolases↗
PubMed1997

Regenerating and sprouting axons differ in their requirements for growth after injury.

After spinal cord injury at birth, axotomized brainstem-spinal and corticospinal neurons are capable of permanent regenerative axonal growth into and through a fetal spinal cord transplant placed into the site of either a spinal cord hemisection or transection. In contrast, if fetal tissue which is not a normal target of the axotomized neurons (embryonic hippocampus or cortex) is placed into a neonatal spinal cord hemisection, brainstem-spinal serotonergic axons transiently innervate the transplant, but subsequently withdraw. The first set of experiments was designed to test the hypothesis that after spinal cord transection, serotonergic axons would cross the nontarget transplant, reach normal spinal cord targets caudal to the transection, and gain access to requisite target-derived cues, permitting permanent maintenance. Surprisingly, after a complete spinal cord transection, brainstem-spinal axons failed to grow into an inappropriate target even transiently. These observations suggest that the transient axonal ingrowth into nontarget transplants may represent lesion-induced axonal sprouting by contralateral uninjured axons. We have used double-labeling with fluorescent dyes, to test directly whether axonal sprouting of neurons which maintain collaterals to uninjured spinal cord targets (1) provide the transient ingrowth of brainstem-spinal axons into a nontarget transplant and (2) contribute to permanent ingrowth into target-specific transplants. Uninjured red nucleus, raphe nucleus, and locus coeruleus neurons extend axons into the nontarget transplant while maintaining collaterals to the host spinal cord caudal to the transplant. The lesion-induced sprouting by uninjured axons was also observed with a target-specific transplant. Taken together, these studies suggest that sprouting and regenerating axons may differ in their requirements for growth after injury.

Animals↗
PubMed1991

Initial stages of retinofugal axon development in the hamster: evidence for two distinct modes of growth.

In order to characterize differences in growth patterns of axons as they elongate toward their targets and during the initial stages of terminal arbor formation within the targets, we examined the primary visual system of fetal and newborn hamsters using three morphological methods: the Cajal-deCastro reduced silver method, the rapid Golgi technique, and anterograde transport of HRP. Axons emerge from the retina between the 10th and 11th embryonic days (E10-E11). The front of retinal axons crosses the chiasm, extends over the primitive dorsal nucleus of the lateral geniculate body (LGBd) by E13, and advances to the back of the superior colliculus (SC) by E13.5-E14. The rate of axon growth during this advance is nearly 2 mm/day. Collateral sprouts appear on axons around E15.5. In the LGBd and SC, these sprouts arise from multiple sites along the parent axons. Only one or a few of the sprouts continue to grow and branch, while others are eliminated. The net rate of axon collateral advance in this second phase is an order of magnitude slower than during the stage of axon elongation. Thus, formation of CNS projections may involve two qualitatively distinct modes of axon growth. The arborization mode contrasts with the elongation mode by the presence of branching, a lack of fasciculation and a slower average rate of extension. The stereotypic direct advance of axons during elongation also differs from the remodelling which occurs during arborization. The delay between axon arrival at targets and onset of arborization could be a reflection of axons "waiting" for a maturational change to occur in the retina or in targets. Arborization in the LGBd and SC is initiated around the same time, implicating the former possibility. However, a slower differentiation of retinal arbors in the SC, in addition to morphological differences of arbors in the two structures, suggests that alterations in substrate factors also play a critical role in triggering the early stages of arbor formation.

Aging↗
PubMed2006

Age-dependent axonal degeneration in an Alzheimer mouse model.

Some neurodegenerative diseases including Alzheimer's disease (AD) and amyotrophic lateral sclerosis (ALS) exhibit prominent defects in axonal transport. These defects can manifest as axonal swellings or spheroids, which correspond to axonal enlargements and aberrant accumulation of axonal cargoes, cytoskeletal proteins and lipids. Recently, a controversial scientific debate focussed on the issue whether Abeta serves as a trigger for aberrant axonal transport in the pathophysiology of AD. Prominent axonopathy has been shown to be induced by overexpression of proteins involved in several neurodegenerative diseases. Neurofilament, apolipoprotein E, Niemann-Pick protein and Tau transgenic mice with axonal trafficking deficits have been reported. Furthermore, motor deficits are frequently observed in patients with AD, which has been attributed to the typical tauopathy in post-mortem brain tissue. In the present report, we analyzed axonal neuropathology in the brain and spinal cord of a transgenic mouse model with abundant intraneuronal Abeta42 production and provide compelling evidence for axonal degeneration. The APP/PS1ki mice showed characteristic axonal swellings, spheroids, axonal demyelination and ovoids, which are myelin remnants of degenerated nerve fibers in an age-dependent manner. Abundant accumulation of intraneuronal N-modified Abeta, Thioflavin S-positive material and ubiquitin was found within the somatodendritic compartment of neurons. We conclude that the intraneuronal accumulation of Abeta-amyloid peptides is followed by axonal degeneration, and thus might be a causative factor for the axonal changes seen in AD.

Adult↗
PubMed2001

Fluororuby as a marker for detection of acute axonal injury in rat spinal cord.

Axonal damage is a common pathological consequence of spinal cord injury. Previous studies have detected axonal injury with silver stains for degeneration or immunohistochemistry for alterations in components such as beta-amyloid precursor protein, neurofilament or ubiquitin. Fluororuby has recently been introduced as a neuronal tracer in studies of spinal cord injury and regeneration. Our study was carried out to determine whether Fluororuby can be used to identify injured axons and monitor the time course of axonal damage. Adult rats underwent needle puncture injury to the white matter in the midline and lateral spinal cord at T11. At the same time, 0.05 microl of Fluororuby was injected into the cord at the same sites. After survival times ranging from 6 h to 3 weeks, spinal cords were cut into longitudinal frozen sections and examined with confocal microscopy. Fluororuby was found to label key features of axonal injury including axonal swelling, retraction balls and disrupted axons. Damaged axons close to the injury site were consistently labeled within 6 h, with indications of swollen and disconnected axons spreading further from the site during the first week. Fewer injured axons were labeled after 1 week survival, but the marker revealed longer distances of degenerating axons both distal and rostral to the injury site. Our findings indicate that Fluororuby is a quick, sensitive, reliable and technically simple fluorescent marker for early stages of acute axonal injury and degeneration.

Acute Disease↗
PubMedDate not supplied

Axonal protein synthesis and transport.

Recent evidence has challenged our ideas about the nature of axonal protein synthesis and transport. Previous metabolic labeling evidence supported the idea that all axonal proteins were synthesized in the cell body and then transported as formed cytoplasmic structures into the axon. Recent evidence suggests that neither the synthesis nor the transport of axonal proteins is that simple. Though most axonal proteins do appear to be synthesized in the neuronal cell body, a small amount of protein appears to be synthesized intra-axonally in some axons. Though small in amount, intra-axonal protein synthesis may be important functionally in some axons. Recent experiments have also begun to identify the presence of a rich array of transport motors in axons, including many members of the kinesin, dynein and myosin families. Progress is being made in identifying which cargoes are being transported by which of these motors. Finally, recent experiments have addressed an old question about whether axoplasmic proteins are transported as filamentous polymers or as soluble components in axons. The answer is that both mechanism can be used in axons. For example, neurofilament protein can move in its particulate or polymeric state, while tubulin can move in its soluble or unpolymerized state.

Axonal Transport↗
PubMedDate not supplied

Axonal mRNAs: functional significance in vertebrates and invertebrates.

Sorting of defined mRNA species to distinct cytoplasmic regions is observed throughout the animal kingdom in many cell types, including neurons. During the past years, mRNA localization to dendrites of nerve cells has been characterized in detail. The functional role of these transcripts appears to be obvious: Since dendrites are equipped with the basic translational machinery, certain proteins are likely to be synthesized on-site. Targeting of mRNAs to the axon of vertebrate neurons is less well understood. Even though some vertebrate nerve cells such as goldfish Mauthner neurons seem to have ribosomes within the axonal compartment, evidence for ongoing local translation is still preliminary. In most differentiated mammalian neurons the axon is thought to lack mRNAs and a protein synthesizing machinery. Although a few nerve cell types harbour substantial amounts of distinct mRNA species within the axonal domain, their functional significance has remained elusive until today. Recent evidence suggests that mRNA transport to neurites including the future axon and local translation might play a role in nerve cell maturation. mRNA targeting to the axon of young neurons is strictly correlated with differentiation. It is no longer observed in fully matured neurons. Finally, for many years invertebrate neurons have served as model systems to investigate axonal mRNA transport and its physiological relevance. There is no doubt that protein synthesis does take place in the axonal domain. However, it has to be considered that invertebrate neurons develop only one type of neurite, referred to as the axon. These axons are different when compared with those of vertebrate nerve cells since they combine characteristics of dendrites and axons. In fact, current evidence supports the view that the axonal mRNAs in invertebrate nerve cells have functions comparable to those of transcripts residing in the dendrites of vertebrate neurons.

Animals↗
PubMed1985

Changes in neurofilament transport coincide temporally with alterations in the caliber of axons in regenerating motor fibers.

The delivery of neurofilaments via axonal transport has been proposed as an important mechanism for regulating axonal caliber. If this hypothesis is correct, alterations in axonal caliber should appear coincident with changes in the delivery of neurofilaments to the axon. The purpose of this study was to determine whether alterations in the caliber of axons in the proximal stumps of transected motor fibers precede, coincide with, or occur substantially later than changes in the delivery of neurofilaments via axonal transport. Between 3 d and 12 wk after crushing the sciatic nerves of 7-wk-old rats, lumbar motor neurons were labeled by the intraspinal injection of [35S]methionine. In neurons labeled between 3 d and 6 wk after axotomy, the relative amount of neurofilament protein in the slow component, as reflected by the ratio of the radioactivities of the 145-kD neurofilament protein to tubulin, was reduced to 30-40% of the control value. Moreover, as determined by immunoreactivity on blots, the amounts of neurofilament protein and tubulin in these nerve fibers were reduced fourfold and twofold, respectively. Thus, changes in the ratio of labeled neurofilament protein to tubulin correlated with comparable changes in the quantities of these proteins in nerve fibers. This decrease in the quantity of neurofilament proteins delivered to axons coincided temporally with reductions in axonal caliber. After regeneration occurred, the delivery of neurofilament proteins returned to pre-axotomy levels (i.e., 8 wk after axotomy), and caliber was restored with resumption of normal age-related radial growth of these axons. Thus, changes in axonal caliber coincided temporally with alterations in the delivery of neurofilament proteins. These results suggest that the majority of neurofilaments in these motor fibers continuously move in the anterograde direction as part of the slow component of axonal transport and that the transport of neurofilaments plays an important role in regulating the caliber of these axons.

Animals↗
PubMed1983

Axonal change in minor head injury.

Anterograde axonal transport of horseradish peroxidase (HRP) in selected cerebral and cerebellar efferents was studied in cats subjected to minor head injury. After trauma, the animals were allowed to survive from one to 24 hours, when they were perfused with aldehydes and processed for the light and electron microscopic visualization of the peroxidase reaction product. By light microscopy, the brain injury elicited an initial intra-axonal peroxidase pooling. With longer post-traumatic survival, HRP pooling increased in size, demonstrated frequent lobulation, and ultimately formed large ball- or club-like swellings which suggested frank axonal separation from the distal axonal segment. Ultrastructural examination revealed that the initial intra-axonal peroxidase pooling was associated with organelle accumulation which occurred without any other form of axonal change or related parenchymal or vascular damage. This accumulation of organelles increased with time and was associated with conspicuous axonal swelling. Ultimately these organelle-laden swellings lost continuity with the distal axonal segment and the axonal swelling was either completely invested by a thin myelin sheath or protruded without myelin investment into the brain parenchyma. This study suggests that axonal change is a consistent feature of minor head injury. Since these axonal changes occurred without any evidence of focal parenchymal or vascular damage, minor brain injury may ultimately disrupt axons without physically shearing or tearing them.

Animals↗
PubMed2006

Herpes simplex virus type 1 accumulation, envelopment, and exit in growth cones and varicosities in mid-distal regions of axons.

The mechanism of anterograde transport of alphaherpesviruses in axons remains controversial. This study examined the transport, assembly, and egress of herpes simplex virus type 1 (HSV-1) in mid- and distal axons of infected explanted human fetal dorsal root ganglia using confocal microscopy and transmission electron microscopy (TEM) at 19, 24, and 48 h postinfection (p.i.). Confocal-microscopy studies showed that although capsid (VP5) and tegument (UL37) proteins were not uniformly present in axons until 24 h p.i., they colocalized with envelope (gG) proteins in axonal varicosities and in growth cones at 24 and 48 h p.i. TEM of longitudinal sections of axons in situ showed enveloped and unenveloped capsids in the axonal varicosities and growth cones, whereas in the midregion of the axons, predominantly unenveloped capsids were observed. Partially enveloped capsids, apparently budding into vesicles, were observed in axonal varicosities and growth cones, but not during viral attachment and entry into axons. Tegument proteins (VP22) were found associated with vesicles in growth cones, either alone or together with envelope (gD) proteins, by transmission immunoelectron microscopy. Extracellular virions were observed adjacent to axonal varicosities and growth cones, with some virions observed in crescent-shaped invaginations of the axonal plasma membrane, suggesting exit at these sites. These findings suggest that varicosities and growth cones are probable sites of HSV-1 envelopment of at least a proportion of virions in the mid- to distal axon. Envelopment probably occurs by budding of capsids into vesicles with associated tegument and envelope proteins. Virions appear to exit from these sites by exocytosis.

Axonal Transport↗