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PubMed1999

Enhanced axonal regeneration following combined demyelination plus schwann cell transplantation therapy in the injured adult spinal cord.

We have treated spinal cord injured rats with demyelination plus Schwann cell transplantation and assessed neurite outgrowth in a quantifiable model of axonal regeneration. Axonal injuries of differing severity were induced in the dorsal funiculus of adult rats using a micromanipulator-controlled Scouten knife. Demyelinated regions were produced so as to overlap with the injury site by the injection of galactocerebroside antibodies plus complement one segment cranial to the axonal injury site. Schwann cells were isolated from the sciatic nerve, expanded in vitro, and transplanted into the injury site 1 day later. Animals were killed after an additional 7 days. Schwann cells were evenly distributed throughout the region of demyelination, which extended 6-7 mm cranial to the axonal injury site. The severity of axonal injury was quantified by counting degenerate axons in transverse resin sections. The degree of axonal regeneration was assessed by an electron microscopic analysis of growth cone frequency and distribution relative to the site of axonal injury. Quantification of growth cones at a distance from the site of axonal injury indicated a strong linear relationship (P < 0.001) between the number of growth cones and the number of severed axons; the ratio of growth cones to severed axons was increased by 26.5% in demyelinated plus transplanted animals compared to demyelinated animals without a transplant. Furthermore, only the demyelinated plus transplanted animals contained growth cones associated with myelin in white matter immediately outside of the region of complete demyelination. Growth cones were absent in transplanted-only animals at a distance from the site of axonal injury. These findings indicate that combined demyelination plus Schwann cell transplantation therapy enhances axonal regeneration following injury and suggests that growth cones are able to overcome myelin-associated inhibitors of neurite outgrowth in the presence of trophic support.

Age Factors↗
PubMed1994

Neuropeptide Y immunoreactive axons in the corpus callosum of the cat during postnatal development.

Many immunocytochemical studies have identified different types of neurotransmitters localized in the corpus callosum (CC) axons in the adult mammal. Few studies have looked at the development of different neurochemically identified CC systems. Previous studies on the development of cat CC axons have indicated that a large number of transitory CC axons project to the cortex during early postnatal development. The present study focuses on the development of one neurochemically identified group of CC axons in the cat, labeled with an antibody against neuropeptide Y (NPY), to determine if this group participates in transitory CC axonal growth. Cats at specified ages from birth to adulthood were studied with a routine method of immunocytochemistry for antiserum to NPY. NPY-immunoreactive (ir) CC axons were detected at all stages examined, from newborn to adult; the peak density occurred during postnatal weeks (PNW) 3-4. During PNW 1-2, the density of NPY-ir CC axons increased gradually; some NPY-ir axons at this age had growth cones located within the CC bundle between the cerebral hemispheres. The density of the NPY-ir CC axons decreased gradually during PNW 5-7, and from PNW 8 to maturity only a few NPY-ir CC axons were observed. These results indicate that at least two types of NPY-ir CC axons (i.e., transitory and permanent) exist during development, and that most of these axons are eliminated or only express NPY-ir for a short period during development. The results also indicate that neurochemical subsets of CC axons participate in the extensive transitory growth observed by means of the membrane tracer DiI but they may follow unique developmental timetables.

Animals↗
PubMed1986

Conduction velocity, size and distribution of optic nerve axons in the turtle, Pseudemys scripta elegans.

Electrophysiological and morphological techniques have been used to characterize optic nerve axons in the red-eared turtle. Three distinct groups of axons are identified on the basis of conduction velocity and axon diameter. The first group (T1) is a small population of axons with large diameters (2.8-4.5 microns) and mean conduction velocities of 13 m/sec. The second group (T2) is a large population of axons with medium diameters (0.4-2.8 microns) and mean conduction velocities of 3 m/sec. The third group (T3) is a medium sized population of small diameter (0.2-0.6 micron), mostly unmyelinated axons with mean conduction velocities of 1 m/sec. There is a significant regional variation in the size, density and myelination of axons in the optic nerve. Large axons are found dorsally and ventrally, while smaller axons and the majority of unmyelinated fibers are found along a dorsotemporal to ventronasal axis through the nerve. Fink-Heimer techniques were used to trace the trajectories of axons of different sizes from the retina to the brain. Large diameter axons can be traced along the dorsal and ventral portions of the optic tract, with a dorsal group leaving the tract in the pretectum and a ventral group entering the basal optic tract. These observations suggest that the distribution of axons within the optic nerve reflects in part the distribution of ganglion cell somata in the retina. However, there is also some segregation of axons of different sizes according to their various central targets.

Action Potentials↗
PubMed1989

Electron microscopic study of the interaction of axons and glia at the site of anastomosis between the optic nerve and cellular or acellular sciatic nerve grafts.

The interactions between retinal ganglion cell (RGC) axons and glia at the site of optic nerve section and at the junctional zone between optic nerve and cellular or acellular peripheral nerve (PN) grafts have been studied electron microscopically. After transection, RGC axons, accompanied by processes of astrocyte cytoplasm, grew out from the proximal optic nerve stump into the scar tissue that developed between proximal and distal stumps. However, axons failed to cross the scar, and none entered the distal stump. By 3 days post lesion (DPL), bundles of RGC axons, accompanied by astrocytes and oligodendrocytes, grew out from the proximal optic nerve stump into the junctional zone between optic nerve and either type of PN graft. The bundles of RGC axons and growth cones that grew towards acellular PN grafts degenerated within 10-20 DPL; by 30 DPL a small number of axons persisted within the end of the proximal optic nerve stump. No axons were seen within the acellular PN grafts. These results suggest that reactive axonal sprouting, axon outgrowth and glial migration from the proximal optic nerve stump are events that occur during an acute response to injury, and that they are independent of the presence of Schwann cells. However, it would appear that few axons entered either scar or junctional zone unless accompanied by glia. There was little evidence that axon outgrowth was laminin-dependent. The bundles that grew towards cellular PN grafts encountered cells that we have identified as Schwann cells within the junctional zone: the axons in these bundles survived and entered the cellular grafts. Schwann cells migrated into the junctional zone from the cellular PN graft. It is probable that Schwann cells facilitated RGC axon entry into the graft directly by both cell contact and the secretion of neuronotrophic factors, and indirectly by modifying the CNS glia in the junctional zone.

Anastomosis, Surgical↗
PubMed2001

Postnatal development of biotinylated dextran amine-labeled corpus callosum axons projecting from the visual and auditory cortices to the visual cortex of the rat.

The distribution and morphology of developing corpus callosum (CC) axons in rat visual cortex was studied by unilateral application of the in vivo anterograde tracer biotinylated dextran amine (BDA) to the visual or auditory cortex of newborns through adults. Changes in the distribution and morphology of CC axons during development were observed. Following BDA placement only in visual cortex, nearly all CC projections were to visual cortex (homotopic CC projections). At postnatal day (PND) 5-8, labeled CC axons were found throughout the contralateral visual cortex, including area 17; these CC axons could be followed from the white matter to layer I. By PND 13, few CC axons were found in medial area 17, indicating the existence of transitory CC axons in area 17 at younger ages. Morphological changes were investigated at the area 17/18a border and showed that CC axon collaterals were not formed until PND 8, and terminal arbors were not visible until PND 13; by PND 17, the adult CC-axon terminal pattern was present. At all ages, only a few heterotopic CC projections from visual to auditory cortex were found in the gray matter, although many labeled CC axons extended laterally into the white matter underlying the auditory cortex. Following BDA placement only in auditory cortex, CC projections to both auditory (homotopic CC projections) and visual (heterotopic CC projections) cortex were observed. At all ages, the homotopic CC projections were present throughout the auditory cortex, but were not distributed homogeneously; densely labeled CC axons showed a distinct columnar organization. The heterotopic CC projections were present in all visual cortical areas, including medial area 17, in significant numbers until PND 24, but were mostly eliminated by PND 28, at which time a labeling pattern similar to the adult was found. Thus, most of the heterotopic CC projections were transitory. The present study confirms the existence of transitory CC axons projecting through all layers of the visual cortex, as revealed by DiI, and extends the DiI results by showing that these transitory CC axons arise from both homotopic and heterotopic origins. Furthermore, different sources of transitory CC axons have different timetables for elimination.

Age Factors↗
PubMed1995

Polyamines promote regeneration of injured axons of cultured rat hippocampal neurons.

Axons of cultured rat hippocampal neurons were injured by local irradiation of laser beam, and the effects of spermine, spermidine and putrescine on neurite regeneration following axonal injury were investigated. The axonal growth was stopped by laser irradiation, but addition of spermine remarkably promoted the axonal re-elongation from the injured site. Spermine affected neither the neurite branching at proximal part of injured axons nor the growth of uninjured dendrites. The effect of spermine was concentration dependent and seen maximally at a concentration of 10(-8) M. Spermidine and putrescine also promoted the axonal re-elongation in a concentration-dependent manner. The effects of three polyamines were very similar, and no additivity was observed when maximally effective concentrations of polyamines were added together, suggesting that they act through a common mechanism. Unlike polyamines, basic fibroblast growth factor (bFGF) did not promote the axonal re-elongation from the injured site, but rather stimulated the formation of axonal branches at proximal part of injured axons, supporting that the promotion of axonal re-elongation is a specific action of polyamines. Concomitant addition of spermine and bFGF additively or synergistically promoted both the axonal re-elongation from the injured site and the branch formation at proximal part of injured axons. These data suggest that polyamines have a capability of promoting axonal regeneration of brain neurons after lesioning.

Animals↗
PubMed1989

Synaptic structure and axon collaterals of type B neurons in bullfrog sympathetic ganglia: intracellular horseradish peroxidase (HRP)-labeling study.

Type B neurons of the bullfrog sympathetic ganglia were examined to confirm the existence of axon collaterals and the distribution of synaptic contacts using the intracellular horseradish peroxidase (HRP) labeling method. The mean diameter of the perikarya was 60.8 (+/- 11.5 standard deviation; n = 36) X 43.8 (+/- 11.3) microns and the mean diameter of the initial segments of axons was 6.0 (+/- 1.8; n = 36) microns. Axon collaterals were found in 6 cells among 36 examined. They branched from axons at 61-167 microns from the perikaryon of origin. Short-axon collaterals containing vesicles (diameter: about 70 nm) were also observed to protrude from the stem axons. Spine-like processes were observed from the cell soma, axon hillock and the initial segment of the axon. They enclosed synaptic axon varicosities, or extended into the extracellular space without any synaptic contact. Serial sections revealed 171 axon varicosities in contact with a single ganglion cell; 32 (18.7%) varicosities were seen on the somata. 66 (38.6%) on the axon hillock and 73 (42.7%) on the initial segment of the axon which extended 100 microns from the perikaryon. Synaptic terminals were also found on the axon as far as 494 microns from the cell body of origin. These findings would provide a morphological basis for interaction between bullfrog sympathetic neurons at pre- or postsynaptic sites.

Animals↗
PubMed1994

Regenerating sciatic nerve axons contain the adult rather than the embryonic pattern of microtubule associated proteins.

Microtubule associated proteins play a central role in the control of axon growth. We have used immunohistochemical techniques to establish which microtubule-associated proteins are present in the rat hindlimb spinal cord, dorsal root ganglia and peripheral nerves during axonal growth during embryogenesis, in adulthood, and during regeneration of crushed sciatic nerves. During embryogenesis microtubule-associated protein-1b and tau are present in all neurons and axons, microtubule-associated protein-2 is present in neurons but not in axons, and there is no microtubule-associated protein-1a. In adults, microtubule-associated protein-1a and microtubule-associated protein-1b are present in all sciatic nerve axons and in motor and dorsal root ganglion neurons. Tau, in its adult form, is present in many fine probably sensory axons, but not in most larger axons, and in motor and sensory neurons. Microtubule-associated protein-2 is present only in neurons. During regeneration the pattern of microtubule-associated protein expression retains the adult pattern. All regenerating axons contain microtubule-associated protein-1a and microtubule-associated protein-1b, none contain microtubule-associated protein-2, and a subset of fine axons contain tau. There is no detectable change in microtubule-associated protein expression by motoneurons. While axons are clearly able to regenerate without either microtubule-associated protein-2 or tau, tau containing axons appear to regenerate faster than those which lack it. It is possible that the failure of neurons to recapitulate the embryonic pattern of microtubule-associated protein expression during regeneration could be a reason why regenerative axon growth is slower and less vigorous than axon growth in embryos.

Animals↗
PubMed1991

Effect of geometrical irregularities on propagation delay in axonal trees.

Multiple successive geometrical inhomogeneities, such as extensive arborization and terminal varicosities, are usual characteristics of axons. Near such regions the velocity of the action potential (AP) changes. This study uses AXONTREE, a modeling tool developed in the companion paper for two purposes: (a) to gain insights into the consequence of these irregularities for the propagation delay along axons, and (b) to simulate the propagation of APs along a reconstructed axon from a cortical cell, taking into account information concerning the distribution of boutons (release sites) along such axons to estimate the distribution of arrival times of APs to the axons release sites. We used Hodgkin and Huxley (1952) like membrane properties at 20 degrees C. Focusing on the propagation delay which results from geometrical changes along the axon (and not from the actual diameters or length of the axon), the main results are: (a) the propagation delay at a region of a single geometrical change (a step change in axon diameter or a branch point) is in the order of a few tenths of a millisecond. This delay critically depends on the kinetics and the density of the excitable channels; (b) as a general rule, the lag imposed on the AP propagation at a region with a geometrical ratio GR greater than 1 is larger than the lead obtained at a region with a reciprocal of that GR value; (c) when the electronic distance between two successive geometrical changes (Xdis) is small, the delay is not the sum of the individual delays at each geometrical change, when isolated. When both geometrical changes are with GR greater than 1 or both with GR less than 1, this delay is supralinear (larger than the sum of individual delays). The two other combinations yield a sublinear delay; and (d) in a varicose axon, where the diameter changes frequently from thin to thick and back to thin, the propagation velocity may be slower than the velocity along a uniform axon with the thin diameter. Finally, we computed propagation delays along a morphologically characterized axon from layer V of the somatosensory cortex of the cat. This axon projects mainly to area 4 but also sends collaterals to areas 3b and 3a. The model predicts that, for this axon, areas 3a, 3b, and the proximal part of area 4 are activated approximately 2 ms before the activation of the distal part of area 4.

Action Potentials↗
PubMed1991

Peanut agglutinin and chondroitin-6-sulfate are molecular markers for tissues that act as barriers to axon advance in the avian embryo.

Axon outgrowth between the spinal cord and the hindlimb of the chick embryo is constrained by three tissues that border axon pathways. Growth cones turn to avoid the posterior sclerotome, perinotochordal mesenchyme, and pelvic girdle precursor during normal development and after experimental manipulation. We wanted to know if these functionally similar barriers to axon advance also share a common molecular composition. Since the posterior sclerotome differentially binds peanut agglutinin (PNA) and since PNA binding is also typical of prechondrogenic differentiation, we examined the pattern of expression of PNA binding sites and cartilage proteoglycan epitopes in relation to axon outgrowth. We found that all three barrier tissues preferentially express both PNA binding sites and chondroitin-6-sulfate (C-6-S) immunoreactivity at the time when growth cones avoid these tissues. Moreover, both epitopes are expressed in the roof plate of the spinal cord and in the early limb bud, two additional putative barriers to axon advance. In contrast, neither epitope is detected in peripheral axon pathways. In the somites, this dichotomous pattern of expression clearly preceded the invasion of the anterior sclerotome by either motor growth cones or neural crest cells. However, in the limb, barrier markers disappeared from presumptive axon pathways in concert with the invasion of axons. Since this coordinate pattern suggested that the absence of barrier markers in these axon pathways requires an interaction with growth cones, we analyzed the pattern of barrier marker expression following unilateral neural tube deletions. We found that PNA-negative axon pathways developed normally even in the virtual absence of axon outgrowth. We conclude that the absence of staining with carbohydrate-specific barrier markers is an independent characteristic of the cells that comprise axon pathways. These results identify two molecular markers that characterize known functional barriers to axon advance and suggest that barrier tissues may impose patterns on peripheral nerve outgrowth by virtue of their distinct molecular composition.

Animals↗
PubMed1998

Functional architecture of primate cone and rod axons.

The cone axon is nearly four times thicker than the rod axon (1.6 vs 0.45 microns diameter). To assess how signal transfer and integration at the terminal depend on cable dimensions, a transducer (cone = ohmic conductance, rod = current source) coupled via passive cable to a sphere with a chloride conductance (representing GABAA receptor) was modelled. For a small signal in peripheral cone with a short axon, steady photosignal transfers independently of axon diameter despite a significant chloride conductance at the cone terminal. Temporally varying photosignal also transfers independently of axon diameter up to 20 Hz and is attenuated only 20% at 50 Hz. Thus, to accomplish the basic electrical functions of a peripheral cone, a thin axon would suffice. For a foveal cone with a long axon steady photosignal transfers independently of axon diameter, but temporally varying photosignal is attenuated 5-fold at 50 Hz for a thick axon and 10-fold for a thin axon. This might contribute to the lower sensitivity of central retina to high temporal frequencies. The cone axon contains 14-fold more microtubules than the rod axon, and its terminal contains at least 20-fold more ribbon synapses than the rod's. Since ribbon synapses sustain high rates of exocytosis, the additional microtubules (which require a thicker axon) may be needed to support a greater flux of synaptic vesicle components.

Animals↗
PubMedDate not supplied

Fast axonal transport of the vesicular acetylcholine transporter (VAChT) in cholinergic neurons in the rat sciatic nerve.

The sciatic nerve, as a part of the peripheral nervous system (PNS), has been used to study axonal transport for decades. It contains motor, sensory as well as autonomic axons. The present study has concentrated on the axonal transport of the synaptic vesicle acetylcholine transporter (VAChT), using the "stop-flow/nerve crush" method. After blocking fast axonal transport by means of a crush, distinct accumulations of various synaptic vesicle proteins, including VAChT, and peptides developed during the first hour after crush-operation and marked increases were observed up to 8 h post-operative. Semiquantitative analysis, using cytofluorimetric scanning (CFS) of immuno-incubated sections, revealed a rapid rate of accumulation proximal to the crush, and that the ratio between distal accumulations (organelles in retrograde transport) and proximal accumulations (organelles in anterograde transport) was about 40%. Most synaptic vesicle proteins were colocalized in the axons proximal to the crush. VAChT-immunoreactive axons were also immunoreactive for choline acetyltransferase (ChAT). Autonomic axons with VAChT also contained VIP-LI. The results demonstrate (1) that VAChT, as well as other synaptic vesicle proteins, is transported with fast axonal transport in motor axons as well as in autonomic post-ganglionic neurons in this nerve, (2) VAChT colocalized in motor axons with SV2 as well as with synaptophysin, indicating storage in the same axonal particle, (3) in the autonomic postganglionic sympathetic cholinergic fibres, VAChT colocalized with VIP, but VIP-LI was present in rather large granular structures while VAChT-LI was present mostly as small granular elements, (4) in motor as well as in autonomic axons ChAT-LI was present in VAChT-positive axons, and (5) the ratio of recycling (retrogradely accumulated) VAChT-IR was about 40%, in contrast to the recycling fraction of synaptophysin that was about 70%.

Animals↗
PubMedDate not supplied

Axonal pathology in myelin disorders.

Myelination provides extrinsic trophic signals that influence normal maturation and long-term survival of axons. The extent of axonal involvement in diseases affecting myelin or myelin forming cells has traditionally been underestimated. There are, however, many examples of axon damage as a consequence of dysmyelinating or demyelinating disorders. More than a century ago, Charcot described the pathology of multiple sclerosis (MS) in terms of demyelination and relative sparing of axons. Recent reports demonstrate a strong correlation between inflammatory demyelination in MS lesions and axonal transection, indicating axonal loss at disease onset. Disruption of axons is also observed in experimental allergic encephalomyelitis and in Theiler's murine encephalomyelitis virus disease, two animal models of inflammatory demyelinating CNS disease. A number of dysmyelinating mouse mutants with axonal pathology have provided insights regarding cellular and molecular mechanisms of axon degeneration. For example, the myelin-associated glycoprotein and proteolipid protein have been shown to be essential for mediating myelin-derived trophic signals to axons. Patients with the inherited peripheral neuropathy Charcot-Marie Tooth disease type 1 develop symptomatic progressive axonal loss due to abnormal Schwann cell expression of peripheral myelin protein 22. The data summarized in this review indicate that axonal damage is an integral part of myelin disease, and that loss of axons contributes to the irreversible functional impairment observed in affected individuals. Early neuroprotection should be considered as an additional therapeutic option for these patients.

Animals↗
PubMed1999

Intraretinal axon diameter: a single cell analysis in the marmoset (Callithrix jacchus).

We have labelled individual retinal ganglion cells of a New World primate, the common marmoset (Callithrix jacchus) with neurobiotin and then measured axon, soma and dendritic field diameter. A total of 111 cells were analysed (62 parasol cells, 22 midget cells, 16 hedge cells and 11 small bistratified cells). When all retinal ganglion cells were grouped together axon diameter was positively correlated to soma diameter. When analysed according to cell class only midget cells showed a positive correlation between soma size and mean axon diameter. Dendritic field diameter and mean axon diameter of both parasol and midget cells showed significant correlations. Axon diameter is not constant along the intraretinal length of the axon and the rate of change in diameter appears to be related to the cell class and the initial size of the axon. Midget cell axons showed a rapid increase of up to 20% over the first 200 microm in contrast to parasol cell axons which increased more slowly over this distance but then showed a marked increase in diameter of up to 40% over the next 450 microm. However, axon diameter did not remain at these increased diameters but decreased at greater distances from the soma. The degree to which an axon changes its diameter is related to retinal ganglion cell class and the initial size of the axon. We postulate that these variations in intraretinal axon diameter may have a direct influence on conduction velocity and reflect a compensatory mechanism to minimise spatiotemporal dispersion along the visual pathway.

Animals↗
PubMed1999

Regrowth of axons into the distal spinal cord through a Schwann-cell-seeded mini-channel implanted into hemisected adult rat spinal cord.

Schwann cells (SCs) have been shown to be a key element in promoting axonal regeneration after being grafted into the central nervous system (CNS). In the present study, SC-supported axonal regrowth was tested in an adult rat spinal cord implantation model. This model is characterized by a right spinal cord hemisection at the eighth thoracic segment, implantation of a SC-containing mini-channel and restoration of cerebrospinal fluid circulation by suturing the dura. We demonstrate that a tissue cable containing grafted SCs formed an effective bridge between the two stumps of the hemicord 1 month after transplantation. Approximately 10 000 myelinated and unmyelinated axons (1 : 9) per cable were found at its midpoint. In addition to propriospinal axons and axons of peripheral nervous system (PNS) origin, axons from as many as 19 brainstem regions also grew into the graft without additional treatments. Most significantly, some regenerating axons in the SC grafts were able to penetrate through the distal graft-host interface to re-enter the host environment, as demonstrated by anterograde axonal labelling. These axons coursed toward, and then entered the grey matter where terminal bouton-like structures were observed. In channels containing no SCs, limited axonal growth was seen within the graft and no axons penetrated the distal interface. These findings further support the notion that SCs are strong promotors of axonal regeneration and that the mini-channel model may be appropriate for further investigation of axonal re-entry, synaptic reconnection and functional recovery following spinal cord injury.

Animals↗
PubMed1987

Neurofilament gene expression: a major determinant of axonal caliber.

Within the wide spectrum of axonal diameters occurring in mammalian nerve fibers, each class of neurons has a relatively restricted range of axonal calibers. The control of caliber has functional significance because diameter is the principal determinant of conduction velocity in myelinated nerve fibers. Previous observations support the hypothesis that neurofilaments (NF) are major intrinsic determinants of axonal caliber in large myelinated nerve fibers. Following interruption of axons (axotomy) by crushing or cutting a peripheral nerve, caliber is reduced in the proximal axonal stumps, which extend from the cell bodies to the site of axotomy. (The distal axonal stumps, which are disconnected from the cell bodies, degenerate and are replaced by the outgrowth of regenerating axonal sprouts arising from the proximal stump). This reduction in axonal caliber in the proximal stumps is associated with a selective diminution in the amount of NF protein undergoing slow axonal transport in these axons, with a decrease in axonal NF content, and with reduced conduction velocity. The present report demonstrates that changes in axonal caliber after axotomy correlate with a selective alteration in NF gene expression. Hybridization with specific cDNAs was used to measure levels of mRNA encoding the 68-kDa neurofilament protein (NF68), beta-tubulin, and actin in lumbar sensory neurons of rat at various times after crushing the sciatic nerve. Between 4 and 42 days after axotomy by nerve crush, the levels of NF68 mRNA were reduced 2- to 3-fold. At the same times, the levels of tubulin and actin mRNAs were increased several-fold. These findings support the hypothesis that the expression of a single set of neuron-specific genes (encoding NF) directly determines axonal caliber, a feature of neuronal morphology with important consequences for physiology and behavior.

Animals↗
PubMed1993

Fate of severed cortical projection axons.

Corticospinal neurons show a primarily degenerative response to axotomy in adult mammals. The long remaining proximal axon with its extensive synaptic contacts may contribute to the lack of initial regenerative response in this cell type. We examined a related group of cortical axons after lesions in the subcortical white matter close to their cell bodies of origin. With cholera B chain conjugated to horseradish peroxidase (CTB-HRP), transcallosal axons projecting into areas of a lesion were labeled. Animals surviving between 2 days and 4 months were examined with both light microscopic and ultrastructural techniques. During the first several days after injury, many of the axon terminals projecting into the lesion site had the appearance of axonal sprouts, although the majority of endings had the appearance of degenerating terminal swellings. By 2 weeks after injury some axonal sprouts had extended a short distance along the margins of the lesions, into overlying cortex. Four weeks after injury there is a reduction in the number of axons extending toward the lesion. This loss of axons appeared progressive and resulted in not only a loss of labeled axons, but also eventually in atrophy of the subcortical white matter near the lesion. In comparison to corticospinal axon lesions in the spinal cord or medullary pyramids, there is more extensive axonal sprouting and elongation after subcortical lesions. Degenerative morphological features still predominate after subcortical lesions and no successful trans-lesion axonal regeneration occurs. Axonal retraction and loss are both accelerated and more extensive after proximal subcortical axotomy than after corticospinal tract lesions.

Animals↗
PubMed1997

Loss of axonal microtubules and neurofilaments after stretch-injury to guinea pig optic nerve fibers.

Axonal swellings, characterized by focal accumulations of membranous organelles at presumed sites of interrupted axonal transport, occur in diffuse axonal injury (DAI) in human, blunt head injury and in animal models of nondisruptive axonal injury. Membranous organelles are transported by fast axonal transport in association with microtubules. Although loss of microtubules has been documented at levels of injury severe enough to result in permeabilization of the axolemma to tracers such as horseradish peroxidase, there has been no detailed analysis of responses by microtubules in less severe or milder forms of nondisruptive axonal injury. To test the hypothesis that in less severe forms of axonal injury there is a rapid response by axonal microtubules that might provide an explanation for loss of fast axonal transport, we have carried out a morphometric analysis of microtubules in CNS axons after stretch-injury. There is loss of microtubules at nodes of Ranvier with nodal blebs within 15 min of injury, and in internodal axonal swellings between 2 and 4 h. There is a return to control values at nodes of Ranvier by 4 h, and at the internode by 24 h. There is no loss of microtubules at paranodes, although there is a reduction in their density in the first 2 h after injury. The greatest loss of microtubules occurs at sites of axolemma infolding. Hypothetical mechanisms that might lead to this loss resulting in focal disruption of fast axonal transport and the formation of axonal swellings are discussed.

Analysis of Variance↗