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PubMed1980

Electrical interactions between the giant axons of a polychaete worm (Sabella penicillus L.).

Intracellular recordings demonstrated a transfer of impulses between the paired giant axons of Sabella, apparently along narrow axonal processes contained within the paired commissures which link the nerve cords in each segment of the body. This transfer appears not to be achieved by chemical transmission, as has been previously supposed. This is indicated by the spread of depolarizing and hyperpolarizing voltage changes between the giant axons, the lack of effects of changes in the concentrations of external divalent cations on impulse transmission and by the effects of hyperpolarization in reducing the amplitude of the depolarizing potential which precedes the action potentials in the follower axon. The ten-to-one attenuation of electronic potentials between the giant axons argues against the possibility of an exclusively passive spread of potential along the axonal processes which link the axons. Observation of impulse traffic within the nerve cord commissures indicates, on the other hand, that transmission is achieved by conduction of action potentials along the axonal processes which link the giant axons. At least four pairs of intact commissures are necessary for inter-axonal transmission, the overall density of current injected at multiple sites on the follower axon being, it is presumed, sufficient to overcome the reduction in safety factor imposed by the geometry of the system in the region where axonal processes join the giant axons. The segmental transmission between the giant axons ensures effective synchronization of impulse traffic initiated in any region of the body and, thus, co-ordination of muscular contraction, during rapid withdrawal responses of the worm.

Action Potentials↗
PubMed2001

Topographic-specific axon branching controlled by ephrin-As is the critical event in retinotectal map development.

The retinotectal projection is the predominant model for studying molecular mechanisms controlling development of topographic axonal connections. Our analyses of topographic mapping of retinal ganglion cell (RGC) axons in chick optic tectum indicate that a primary role for guidance molecules is to regulate topographic branching along RGC axons, a process that imposes unique requirements on the molecular control of map development. We show that topographically appropriate connections are established exclusively by branches that form along the axon shaft. Initially, RGC axons overshoot their appropriate termination zone (TZ) along the anterior-posterior (A-P) tectal axis; temporal axons overshoot the greatest distance and nasal axons the least, which correlates with the nonlinear increasing A-P gradient of ephrin-A repellents. In contrast, branches form along the shaft of RGC axons with substantial A-P topographic specificity. Topography is enhanced through the preferential arborization of appropriately positioned branches and elimination of ectopic branches. Using a membrane stripe assay and time-lapse microscopy, we show that branches form de novo along retinal axons. Temporal axons preferentially branch on their topographically appropriate anterior tectal membranes. After the addition of soluble EphA3-Fc, which blocks ephrin-A function, temporal axons branch equally on anterior and posterior tectal membranes, indicating that the level of ephrin-As in posterior tectum is sufficient to inhibit temporal axon branching and generate branching specificity in vitro. Our findings indicate that topographic branch formation and arborization along RGC axons are critical events in retinotectal mapping. Ephrin-As inhibit branching along RGC axons posterior to their correct TZ, but alone cannot account for topographic branching and must cooperate with other molecular activities to generate appropriate mapping along the A-P tectal axis.

Animals↗
PubMed1992

Synapses formed by identified retinogeniculate axons during the segregation of eye input.

The synaptic organization of identified retinogeniculate axons was studied during the prenatal development of eye-specific layers in the LGN of the cat. During this period, retinogeniculate axons undergo stereotyped morphological changes. Retinogeniculate axons originating from one eye and passing through LGN territory destined to be solely innervated by the other eye (inappropriate territory) initially give rise to many side branches. As the eye-specific layers emerge, these axons elaborate extensive terminal arbors within territory appropriate to their eye of origin and concurrently retract their side branches from inappropriate territory (Sretavan and Shatz, 1986). These transient side branches may therefore represent a morphological substrate for the observed functional convergence of inputs from the two eyes onto common LGN neurons during prenatal development (Shatz and Kirkwood, 1984). This possibility was investigated by examining whether identified axons and their side branches form synapses in inappropriate territory. Three retinogeniculate axons from two fetuses aged embryonic day 53 (E53) and E57 were filled with HRP in an in vitro preparation, prior to being processed for electron microscopy (EM). The HRP-filled axons, originating from the contralateral eye, were first reconstructed at the light microscope level. The portion of axon passing through the center of ipsilaterally innervated layer A1 was then serially sectioned and reconstructed by EM. Two sets of 450 serial EM sections revealed that all three contralateral axons established synaptic contacts in ipsilateral territory. Many of these synapses were made by side branches and a few were even formed by the main axon trunks. Both side branches and trunks formed mainly en passant asymmetrical contacts that were associated with spherical synaptic vesicles and that were apposed to immature dendritic elements and dendritic shafts. For comparison, a portion of the same E53 axon within the future contralateral layer A was also serially sectioned and reconstructed for EM. Within this contralateral zone, the E53 axon formed synaptic contacts similar to those established in the ipsilateral region, except that in the appropriate zone they contained significantly more synaptic vesicles. These results demonstrate that axons from the contralateral eye can establish synapses in territory simultaneously innervated by the ipsilateral eye, both via side branches and by means of contacts along the main axon trunk. Thus, the development of eye-specific layers is accompanied by the formation and subsequent elimination of synapses that almost certainly represent a morphological substrate for the known transient functional convergence of inputs from the two eyes.

Animals↗
PubMed1990

Specific routing of retinal ganglion cell axons at the mammalian optic chiasm during embryonic development.

During development of the mammalian CNS, axons encounter multiple pathway choices on their way to central target structures. A major pathway branch point in the visual system occurs at the optic chiasm, where retinal ganglion cell axons may either enter the ipsilateral or the contralateral optic tract. To investigate whether embryonic mouse retinal ganglion cell axons, upon reaching the optic chiasm, selectively grow into the correct pathway, developing retinal ganglion cells were retrogradely labeled using either 1,1'-dioctadecyl- 3,3,3',3'-tetramethylindocarbocyanine perchlorate (Dil) or fluorescent microspheres placed into the optic tract on one side. The distribution of ipsilaterally and contralaterally projecting ganglion cells in the embryo was then examined and compared to that of the adult animal. Results show that axon routing at the chiasm is already extremely adult-like as early as embryonic day 15 (E15), shortly after retinal axons arrive at the chiasm. [Retinal ganglion cell neurogenesis = E11-E18 (Drager, 1985); birth = E21.] Throughout the development of this pathway, routing errors are infrequent and are on the order of only about 3-8/1000 retinal ganglion cells. Thus, embryonic retinal ganglion cell axons do not project randomly at the optic chiasm but instead appear to be highly specific in their choice of pathway. To learn how correct pathway choices are made, retinal axons were retrogradely labeled with Dil and their trajectories at the optic chiasm were reconstructed. Results show that ipsilaterally and contralaterally projecting axons are highly intermixed as they enter the chiasm region but selectively grow into the correct pathway. For example, a contralaterally projecting axon near the entrance of the ipsilateral optic tract will turn and bypass this pathway and grow towards the midline to head into the contralateral optic tract. Similarly, axons far away from the ipsilateral optic tract frequently turn abruptly at right angles to enter the ipsilateral tract, directly crossing over contralaterally projecting axons heading to the opposite side. The sorting out of intermixed ipsilaterally and contralaterally projecting retinal axons into the appropriate optic tracts strongly suggests the presence of specific guidance cues at the optic chiasm during embryonic development. Together, results from this study demonstrate that the pattern of axon projection at the adult mammalian optic chiasm is gradually built upon a highly specific pattern of axon routing laid down early during development.

Animals↗
PubMed1990

Axon overproduction and elimination in the corpus callosum of the developing rhesus monkey.

We have studied the cytological and quantitative aspects of axon addition and elimination in the corpus callosum of the developing rhesus monkey. Electron microscopic analysis reveals that during fetal development the number of callosal axons increases from 4 million at embryonic day 65 (E65) to 188 million at birth (E 165). Thus, the number of callosal axons in newborn monkeys exceeds the number present in the adult (an average of 56 million; LaMantia and Rakic, 1990a) by at least 3.5 times. Although there is some variability among the 11 fetal and newborn monkeys examined, there appears to be a progressive increase in the total number of callosal axons from midgestation through birth. The presence and numbers of growth cones from E65 through birth suggests that axon addition occurs exclusively during this period. There is no ultrastructural or quantitative indication of postnatal axon addition. After birth, about 70% of the axons in the callosum are eliminated in 2 phases. During the first phase, which includes the first 3 postnatal weeks, approximately 80 million axons are lost at an estimated rate of 4.4 million/d or 50/sec. During the second phase, which continues for the following 3 months, an additional 50 million axons are eliminated at a rate of 0.5 million/d or 5/sec until the adult value is reached. A discontinuous distribution of different classes of axons along the anterior-posterior axis of the tract reminiscent of the pattern seen in the adult is detectable before the onset of the first phase of axon elimination. Since the basic topography and terminal field patterns of callosal projections are well established before birth in all regions of the monkey cortex examined so far (Goldman-Rakic et al., 1983; Killackey and Chalupa, 1986; Dehay et al., 1988; Schwartz and Goldman-Rakic, 1990), we conclude that the massive postnatal elimination of callosal axons described here is unlikely to play a significant role in the development of discretely patterned callosal projection zones or their columnar terminations. The coincidence of axon elimination and the increase in synaptic density throughout the primate cerebral cortex during the first 6 postnatal months (Rakic et al., 1986), however, suggests that supernumerary axons may be lost during a process that results in the local proliferation of synapses from a subset of initial interhemispheric projections.

Aging↗
PubMed1994

NGF and NT-3 have differing effects on the growth of dorsal root axons in developing mammalian spinal cord.

The functions of neurotrophins in relation to axon growth and branching during development of the nervous system are unknown. In order to address this question, we have investigated the influences of systemically administered mouse nerve growth factor (mNGF) and human recombinant neurotrophin-3 (hrNT-3) on dorsal root axon growth in the spinal cord of embryonic rats. As anticipated, mNGF has a marked influence on growth of dorsal root axons. In mNGF-treated animals, dorsal root axons in the developing dorsal funiculi and axon collaterals in developing gray matter are substantially longer than those of age-matched controls. Furthermore, growth cones of some dorsal root axons have more than twice the surface area of controls. These effects of NGF are highly selective. Dorsal root axons that occupy a lateral position in white matter and that normally give off collaterals to superficial dorsal horn are prominently affected. Axons that run medially in dorsal columns and that give off collaterals to laminae III and IV and the ventral horn are not demonstrably influenced by treatment with exogenous mNGF. In contrast to the striking effects of mNGF on dorsal root axon growth, the influences of hrNT-3 were considerably more complex. Administration of hrNT-3 increased the mean soma area of DRG neurons, particularly those at the larger end of the size spectrum, consistent with its hypothesized role as a growth factor for proprioceptive sensory neurons. However, in striking contrast to the actions of mNGF, hrNT-3 consistently inhibited axon collateral growth in gray matter at early developmental stages. At later stages, we could not discern a clear-cut influence of hrNT-3 on dorsal root axon growth and branching. We conclude that the ability of mNGF to stimulate axon growth in both white and gray matter is consistent with the idea that mNGF regulates the developing axonal projections of DRG neurons in vivo. In contrast, systemically administered hrNT-3 inhibits the axon collateralizations of DRG neurons in gray matter at early developmental stages. We hypothesize that this inhibitory effect may be related to disruption of a chemotropic gradient of NT-3, or to the widespread expression of the NT-3 receptor trkC, on non-neuronal cells.

Animals↗
PubMed1997

Xefiltin, a Xenopus laevis neuronal intermediate filament protein, is expressed in actively growing optic axons during development and regeneration.

Neurofilaments are an important structural component of the axonal cytoskeleton and are made of neuronal intermediate filament (nIF) proteins. During axonal development, neurofilaments undergo progressive changes in molecular composition. In mammals, for example, highly phosphorylated forms of the middle- and high-molecular-weight neurofilament proteins (NF-M and NF-H, respectively) are characteristic of mature axons, whereas nIF proteins such as alpha-internexin are typical of young axons. Such changes have been proposed to help growing axons accommodate varying demands for plasticity and stability by modulating the structure of the axonal cytoskeleton. Xefiltin is a recently discovered nIF protein of the frog Xenopus laevis, whose nervous system has a large capacity for regeneration and plasticity. By amino acid identity, xefiltin is closely related to two other nIF proteins, alpha-internexin and gefiltin. alpha-Internexin is found principally in embryonic axons of the mammalian brain, and gefiltin is expressed primarily in goldfish retinal ganglion cells and has been associated with the ability of the goldfish optic nerve to regenerate. Like gefiltin in goldfish, xefiltin in Xenopus is the most abundantly expressed nIF protein of mature retinal ganglion cells. In the present study, we used immunocytochemistry to study the distribution of xefiltin during optic nerve development and regeneration. During development, xefiltin was found in optic axons at stage 35/36, before they reach the tectum at stage 37/38. Similarly, after an orbital crush injury, xefiltin first reemerged in optic axons after the front of regeneration reached the optic chiasm, but before it reached the tectum. Thus, during both development and regeneration, xefiltin was present within actively growing optic axons. In addition, aberrantly projecting retinoretinal axons expressed less xefiltin than those entering the optic tract, suggesting that xefiltin expression is influenced by interactions between regenerating axons and cells encountered along the visual pathway. These results support the idea that changes in xefiltin expression, along with those of other nIF proteins, modulate the structure and stability of actively growing optic axons and that this stability is under the control of the pathway which growing axons follow.

Animals↗
PubMed2004

Pax6 guides a relay of pioneer longitudinal axons in the embryonic mouse forebrain.

We have characterized a system of early neurons that establish the first two major longitudinal tracts in the embryonic mouse forebrain. Axon tracers and antibody labels were used to map the axon projections in the thalamus from embryonic days 9.0-12, revealing several distinct neuron populations that contributed to the first tracts. Each of the early axon populations first grew independently, pioneering a short segment of new tract. However, each axon population soon merged with other axons to form one of only two shared longitudinal tracts, both descending: the tract of the postoptic commissure (TPOC), and, in parallel, the stria medullaris. Thus, the forebrain longitudinal tracts are pioneered by a relay of axons, with distinct axon populations pioneering successive segments of these pathways. The extensive merging of tracts suggests that axon-axon interactions are a major guidance mechanism for longitudinal axons. Several axon populations express tyrosine hydroxylase, identifying the TPOC as a major pathway for forebrain dopaminergic projections. To start a genetic analysis of pioneer axon guidance, we have identified the transcription factor Pax6 as critical for tract formation. In Pax6 mutants, both longitudinal tracts failed to form due to errors by every population of early longitudinal axons. Taken together, these results have identified potentially important interactions between series of pioneer axons and the Pax6 gene as a general regulator of longitudinal tract formation in the forebrain.

Animals↗
PubMed1990

Axo-axonic chandelier cells in the rat fascia dentata: Golgi-electron microscopy and immunocytochemical studies.

Synaptic transmission can be blocked very efficiently by inhibitory synapses on axon initial segments. Inhibitory chandelier cells forming synapses on the axon initial segment of pyramidal neurons have been found in the neocortex and hippocampus proper. Here we describe an axo-axonic local circuit neuron in the rat fascia dentata that establishes synaptic contacts with axon initial segments of numerous dentate granule cells. Examination of a large number of Golgi-impregnated nongranule cells in the fascia dentata of rats revealed a group of neurons with characteristics of chandelier cells. Thus these cells exhibited an extensive axonal plexus within the granular layer that characteristically formed vertical aggregations of axonal varicosities. The cell bodies of these neurons were located in the inner molecular layer or in the outer part of the granular layer. Their dendrites invaded the molecular layer, suggesting an afferent innervation similar to that of the granule cells. Well impregnated putative axo-axonic cells were gold-toned for an electron microscopic analysis. The cell bodies and dendrites of these neurons exhibited characteristic ultrastructural features of nongranule cells, i.e., large amounts of perinuclear cytoplasm, infoldings of the nuclear membrane, and a large number of synaptic contacts on the perikaryon and on the smooth dendritic shafts. The axon originating from the cell body or from a proximal dendrite gave rise to numerous vesicle-filled varicosities that almost exclusively formed symmetric synaptic contacts with axon initial segments. A semiquantitative study of five axonal complexes demonstrated that 92.3% of identified postsynaptic elements were initial segments of granule cell axons. Immunostaining with antibodies against glutamate decarboxylase (GAD) and parvalbumin (PARV) revealed a subpopulation of neurons that very much resembled the Golgi-impregnated axo-axonic cells with regard to cell body location, dendritic arborization, and fine structural characteristics of perikarya and dendrites. GAD and PARV were found to be coexistent in these cells. Moreover, we found GAD- and PARV-immunoreactive terminals in symmetric synaptic contact with axon initial segments of granule cells. The present study has shown a hitherto unknown axo-axonic cell in the rat fascia dentata. On the basis of our immunocytochemical findings, we hypothesize that this cell exerts a strong inhibitory effect on dentate granule cells. This way, signal transmission from the fascia dentata to the hippocampus proper within the "trisynaptic pathway" can efficiently be controlled by a group of highly specialized neurons.

Animals↗
PubMed2002

Computer-assisted morphometric analysis of intrinsic axon terminals in the supragranular layers of cat striate cortex.

Qualitative and quantitative analyses of terminal arborizations of biocytin-labeled axon terminals were carried out in the cat primary visual cortex (V1). Extracellular iontophoretic injections of 5% biocytin were made into V1 of five adult cats. The animals were perfused 24-48 h after the injections. Labeled-axon fragments were considered to comprise two presumptive groups, according to the qualitative features, thickness, bouton features and appearance of terminal arbors. Forty axon fragments (20 for each presumptive group) were digitized using a microscope with motorized stage and a z-encoder, attached to a microcomputer. The densities of boutons, branching points and axon segments per mm of axon as well as axon segment length were used for comparison of the two groups. The two qualitative groups were confirmed to contain two axon types (I and II), according to cluster analysis of characteristics of the 40 axons in our sample. Forward stepwise discriminant analysis retained two variables as predictors of group membership: axonal length and bouton density. Parametric and non-parametric tests were employed for statistical comparisons (significance at P < 0.01). Type II axon fragments showed the greatest densities of boutons, axonal segments and branching points and the smallest values of length of segments ( P < 0.01). Both the qualitative and quantitative differences found for both types of axons suggest that they belong to different functional classes of neurons, namely spiny (type I) and smooth neurons (type II). Computer-assisted morphometric analysis of individual axon fragments seems to be a suitable approach with which different axon types can be objectively distinguished from each other.

Animals↗
PubMed1989

Immunohistochemical analysis of the neurotoxic effects of DSP-4 identifies two populations of noradrenergic axon terminals.

N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine (DSP-4) is a potent and highly selective neurotoxin which induces degeneration of noradrenergic axons. The effects of DSP-4 vary considerably in different brain regions: the drug produces nearly complete depletion of noradrenaline in neocortex, hippocampus, cerebellum and spinal cord, but only partial depletion in hypothalamus and brainstem. In this study we have employed an immunohistochemical method to assess the neurotoxic effects of DSP-4 on the structural integrity of central noradrenergic neurons in the rat, and to identify those noradrenergic axons that remain in the central nervous system 2-4 weeks after DSP-4 treatment. The staining results identified noradrenergic axon terminals as the principal site of action of DSP-4; noradrenergic cell bodies and preterminal axons were not noticeably affected. DSP-4 produced an almost all or none neurotoxic effect on noradrenergic axon terminals in different brain regions. Nearly all noradrenergic axon terminals were destroyed in the neocortex, hippocampus, olfactory bulb, thalamus, tectum, cerebellum and spinal cord dorsal horn. In contrast, most noradrenergic axons were unaffected in the basal forebrain, hypothalamus, reticular formation, brainstem motor nuclei and spinal cord ventral horn. These remaining noradrenergic axon terminals differed morphologically from sensitive axons by their thickness, size and spacing of their varicosities and their dense arborizations within terminal fields. The distribution of noradrenergic axons susceptible to DSP-4 correlates very closely with the distribution of locus coeruleus axons and possibly all regions in which noradrenergic terminals are unaffected by DSP-4 receive their major noradrenergic input from non-locus coeruleus neurons. This study provides the first direct evidence that DSP-4 destroys noradrenergic axon terminals from the locus coeruleus, but not those from non-locus coeruleus neurons. This profound differential sensitivity of noradrenergic axons to DSP-4 is matched by distinct differences in their morphology and their topographic projections. The results support the view that locus coeruleus and non-locus coeruleus noradrenergic neurons constitute two separate subsystems, which differ not only in their projections but also with respect to the pharmacological properties of their axon terminals.

Animals↗
PubMed1991

Organization, Development and Enucleation-induced Alterations in the Visual Callosal Projection of the Hamster: Single Axon Tracing with Phaseolus vulgaris leucoagglutinin and Di-I.

The distribution of callosal axons interconnecting lateral area 17 and medial area 18 of the rodent's occipital cortex is dramatically altered by neonatal enucleation, but it is not known how this manipulation affects the morphology of individual callosal axons or whether the enucleation-induced changes in this pathway reflect maintenance of a transient developmental state by these fibres. In the present study, these questions were addressed by tracing the individual callosal axons in normal adult and neonatally enucleated adult hamsters with Phaseolus vulgaris leucoagglutinin (PHAL) and by anterograde labelling of developing callosal axons with the carbocyanine dye, Di-I. In normal adults, injections of PHAL into the region of the 17 - 18a border produced dense labelling in all layers in the region of the contralateral 17 - 18a border. Larger injections resulted in callosal labelling that extended across the lateral one-half of area 17, primarily in layers I and V. Thirty-four callosal axons from normal adult hamsters were reconstructed through all the cortical laminae. Most of these had very simple terminal arbors. They gave off short collaterals in the infragranular layers and branched more extensively in the uppermost part of layer II - III and in lamina I. Small injections of PHAL into the occipital cortex of neonatally enucleated adult hamsters resulted in labelled axons throughout most of areas 17 and 18a in the contralateral hemisphere. The terminal arbors of most individual callosal axons in eyeless hamsters were not appreciably different from those in sighted animals. However, 26.8% of 28 fibres reconstructed through all cortical laminae in the neonatally enucleated hamsters had much more widespread branches than any of the axons recovered from normal hamsters. As a result, the average total length of the callosal axons from the blinded hamsters was significantly greater than that for such fibres from the sighted animals. Anterograde labelling with Di-I demonstrated axons in the anterior commissure and anterior part of the corpus callosum on P-0. Labelled fibres extended into the white matter underlying the occipital cortex on P-1 and entered the cortical plate on P-2. Some of these axons reached into the marginal layer. Many developing callosal axons had short branches in the white matter, but generally extended only a single collateral into the cortical grey matter. Callosal axons in perinatal animals branched very little within the cortex and, in this respect, resembled fibres labelled with PHAL in adult hamsters. These results support the conclusion that the expanded tangential distribution of the occipital callosal projection in neonatally enucleated adult hamsters results, at least in part, from individual axons with abnormally widespread terminal arbors which are not present in large numbers at any time during normal development.

Journal Article↗
PubMed2006

EphB3: an endogenous mediator of adult axonal plasticity and regrowth after CNS injury.

Endogenous mechanisms underlying the remodeling of neuronal circuitry after mammalian CNS injury or disease remain primarily unknown. Here, we investigated axonal plasticity after optic nerve injury and found that macrophages recruited into the injury site and adult retinal ganglion cell (RGC) axons, which undergo injury-induced sprouting and terminal remodeling, were linked by their respective expression of a ligand and receptor pair active in axon guidance. Recruited macrophages specifically upregulated mRNA encoding the guidance molecule EphB3 and expressed EphB proteins capable of binding Ephrin B molecules in vivo and in vitro. Injured adult RGC axons in turn expressed EphrinB3, a known receptor for EphB3, and RGC axons bound recombinant EphB3 protein injected into the optic nerve. In vitro, EphB3 supported adult RGC axon outgrowth, and axons turned toward a source of this guidance molecule. In vivo, both reduction of EphB3 function in adult heterozygous animals and loss of function in homozygous animals greatly decreased RGC axon re-extension or sprouting after optic nerve injury. Comparisons of axon re-extension in EphB3 null and wild-type littermates showed that this loss of axonal plasticity was not attributable to a difference in intrinsic axon growth potential. Rather, the results indicated an essential role for local optic nerve-derived EphB3 in regulating adult RGC axon plasticity after optic nerve injury. Of note, the loss of EphB3 did not affect the ability of injured RGC axons to elaborate complex terminal branching, suggesting that additional EphB3-independent mechanisms governed adult axon branching triggered by CNS damage.

Animals↗
PubMed2000

A morphometric study of optic axons regenerated in a sciatic nerve graft of adult rats.

PURPOSE: In the present study we have morphometrically examined a regeneration model in which axons normally residing in CNS have regrown and are interacting with Schwann cells from the PNS. This study will not only provide morphometric data on regenerated optic fibers but also shed light on possible factors in determining the fiber morphometry. METHODS: The optic nerves of rats aged 6 weeks were cut intra-orbitally and replaced with a autologous sciatic nerve. After a survival period of 9 months, the graft or "regenerated" nerves containing the regenerated optic axons and Schwann cells were processed for morphometric measurements. RESULTS: The mean myelinated axon diameter of regenerated nerve (1.8 +/- 0.2 micro m) was significantly (P < 0.05) greater than that of the optic nerve (0.9 +/- 0.03 micro m). However, unmyelinated regenerated optic axons had a smaller mean axon diameter (0.49 +/- 0.04 micro m) than normal myelinated optic axons. This may suggest that myelinating glial cells exert an influence on axon caliber and Schwann cells seem to have greater effect than oligodendrocytes. The mean g-ratio showing the relative myelin sheath thickness was found to be the highest in the optic nerve (0.78 +/- 0.003), least in the sciatic nerve (0.6 +/- 0.009) and intermediate in the regenerated nerve (0.68 +/- 0.01). The results indicated that Schwann cells myelinating the regenerated optic axons have produced a thinner myelin sheath. Intra-axonally, no significant difference was detected in the number of axonal microtubules and neurofilaments between the regenerated and optic nerves. Therefore the disposition of microtubules and neurofilaments into axon may be intrinsically determined. CONCLUSIONS: In this study, we have identified some of the extrinsic and intrinsic factors in determining the fiber morphometry of the regen-erated nerve. The axon-size and myelination by glial cells were determined through the external axon-glial interactions, whereas the number of axonal microtubules and neurofilaments were intrinsically determined.

Journal Article↗
PubMed1991

Position of axons in the cat's optic tract in relation to their retinal origin and chiasmatic pathway.

The positions of the crossed and uncrossed optic axons of distinct diameter classes has been examined in the optic tract of the adult cat. In addition, the retinal origin of axons occupying different positions within the tract has been studied. Since the position of a fibre within the optic tract reflects its time of arrival during development, we have used axonal position as an indicator of age and have related this to the chiasmatic pathway choice of the axons. Cats were either monocularly enucleated, to reveal the position and diameter of surviving crossed and uncrossed optic axons in semithin and thin sections, or implants of horseradish peroxidase (HRP) were placed so as to retrogradely label the ganglion cells giving rise to axons within the deep (early arriving), or superficial (later arriving) parts of the tract selectively. This was accomplished by either 1) surgically implanting HRP into the superficial portion of the optic tract, via a transbuccal approach, or 2) making such a transbuccal transection of the superficial fibres, followed by intracerebral injections of HRP to retrogradely label the surviving, deeper, optic axons from their target nuclei. The deep parts of the optic tract contain fine and medium, crossed and uncrossed axons arising from mainly medium sized cells in the contralateral nasal and the ipsilateral temporal retina; there is a clear line of decussation. In contrast, the superficial parts of the tract contain mainly fine diameter axons arising from small cells in the whole contralateral retina, and a small proportion of large diameter axons arising from large, alpha cells in the whole contralateral retina and in the ipsilateral temporal retina. The likelihood that axons from the temporal retina will project contralaterally therefore increases as development proceeds, since these axons are found in the superficial parts of the tract only. This suggests that a time-dependent signal that weakens with age is responsible for directing early arriving optic axons from the temporal retina to take an exclusively uncrossed course.

Animals↗
PubMed1991

Spinal distribution of ascending lamina I axons anterogradely labeled with Phaseolus vulgaris leucoagglutinin (PHA-L) in the cat.

The location of the ascending axons of spinal lamina I cells was studied in cats that received injections of Phaseolus vulgaris leucoagglutinin (PHA-L) in the superficial dorsal horn of the cervical or lumbosacral enlargement. Lamina I axons that could be ascribed to the spinothalamic tract (STT) were of particular interest. The cases were divided into three sets: in seven optimal cases the injections were restricted to lamina I; in ten nominal cases the injections involved laminae I-II or laminae I-III and occasionally lamina IV; and in eight mixed cases laminae I-V were injected. Since ipsilateral propriospinal and bilateral supraspinal axons originate from laminae I and V, but only ipsilateral propriospinal axons from laminae II-IV, this categorization facilitated a comparative analysis. Ascending axons labeled immunohistochemically with avidin/Texas Red were observed in oblique transverse sections from the C1, C3/4, T6, T12, and L3/4 levels. Incidental axonal labeling occurred in the ipsilateral dorsal columns because of passing primary afferent fiber uptake and, in nominal and mixed cases with involvement of laminae III-IV, in the superficial dorsolateral funiculus at the location of the spinocervical tract. Ipsilateral ascending lamina I axons in optimal cases were located in Lissauer's tract and in the white matter adjacent to the dorsal horn. Since these appeared to terminate in lamina I, and few remained at C1, they were ascribed to propriospinal projections. Contralateral ascending lamina I axons in optimal and nominal cases were distributed throughout the dorsal and ventral portions of the lateral funiculus (LF), but, despite considerable variability between animals in their location and dispersion, they were consistently concentrated in the middle of the LF (i.e., at the level of the central canal). This concentration was observed in a slightly more ventral location at C1, and a similar but weaker concentration of lamina I axons was located slightly more dorsally in C1 on the ipsilateral side. These supraspinal lamina I projections were ascribed to the spinomesencephalic tract (SMT) and to the STT. In mixed cases, additional ascending axons ascribed to lamina V cells were labeled in the ventrolateral and ventral funiculi. Many labeled axons were found in this region following a large injection of biocytin into lumbosacral laminae V-VIII in a supplementary case. These results thus together support previous descriptions of a dorsoventral distribution of STT axons according to laminar origin, but they contradict recent reports that lamina I axons ascend in the dorsolateral funiculus.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗
PubMed1994

Ultrastructural studies of diffuse axonal injury in humans.

Diffuse axonal injury (DAI) is observed commonly in traumatically brain injured humans. However, traditional histologic methods have proven of limited use in identifying reactive axonal change early (< 12 h) in the posttraumatic course. Recently, we have reported, in both humans and animals, that antibodies targeting neurofilament subunits are useful in the light microscopic recognition of early reactive change. In the present study, we extend our previous efforts in humans by analyzing the progression of traumatic brain injury (TBI)-induced axonal change at the ultrastructural level. This effort was initiated to follow the subcellular progression of reactive axonal change in humans and to determine whether this progression parallels that described in animals. Two commercially prepared antibodies were used to recognize reactive axonal change in patients surviving from 6 to 88 h. The NR4 antibody was used to target the light neurofilament subunit (NF-L), and the SMI32 antibody was used to target the heavy neurofilament subunit (NF-H). Plastic-embedded tissue sections were screened for evidence of reactive axonal change, and once identified, this reactive change was analyzed at the ultrastructural level. At 6 h survival, focally enlarged, immunoreactive axons with axolemmal infolding or disordered neurofilaments were seen within fields of axons exhibiting no apparent abnormality. By 12 h, some axons exhibited continued neurofilamentous misalignment, pronounced immunoreactivity, vacuolization, and, occasionally, disconnection. At later stages, specifically 30 and 60 h survival, further accumulation of neurofilaments and organelles had led to the further expansion of the axis cylinder, and clearly disconnected reactive swellings were recognized. These contained a dense core of disordered immunoreactive neurofilaments partially encompassed by a cap of less densely aggregated organelles. At 88 h, the reactive axons were larger and elongated, consistent with the continued delivery of organelles by axoplasmic transport. At the later time points, considerable heterogeneity was observed, with focally enlarged disconnected axons being observed in relation to axons showing less advanced reactive change. Our findings suggest that neurofilamentous disruption is a pivotal event in axonal injury.

Adult↗
PubMed2003

Response of mitochondrial traffic to axon determination and differential branch growth.

Mitochondria are concentrated in regions of the neuron where the demand for mitochondrial function is high, such as nodes of Ranvier, synapses, and active growth cones. Does mitochondrial transport respond to changes in neuronal energy consumption and architecture, or does it precede and perhaps predict them? We have used axon determination, elongation, and alternating branch growth in hippocampal neurons to analyze the cellular cues that control mitochondrial traffic. During the stage 2-3 transition, when one minor process becomes the axon and accelerates its growth, mitochondria do not uniformly cluster at the base of the prospective axon. There is increased entry of mitochondria into the nascent axon, but this does not require accumulation near the axon. After axonal elongation is under way, the mitochondrial density of the minor processes decreases. Axonal towing experiments showed that elongation alone does not result in transport of mitochondria into the axon; thus, cytoplasmic flow cannot explain the entry of mitochondria into growing axons. Analysis of mitochondrial transport during alternating growth of axonal branches showed that mitochondrial traffic responds to changes in growth through regulation of entry into, but not exit from, branches. Branch-towing experiments showed that this response is not caused by axonal elongation alone, nor does it require an active growth cone. We propose that mitochondrial traffic in axons responds to changes in axonal outgrowth, and that the mechanism by which sorting at branch points occurs is different from the mechanism responsible for concentrating mitochondria at the growth cone.

Animals↗