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PubMed2002

Entorhinal axons exhibit sprouting in CA1 subfield of the adult hippocampus in a rat model of temporal lobe epilepsy.

Intracerebroventricular kainic acid administration in rat, a model of temporal lobe epilepsy, results in CA3 pyramidal neuron degeneration leading to deafferentation of CA1 pyramidal neurons. Denervation in CA1 shows a near-complete recovery of synaptic density over 2-3 months, but the source of axons participating in the reinnervation is not clear. This study investigated the contribution of the entorhinal cortex in this reinnervation by comparing the distribution of the entorhinal axons in the CA1 subfield between the intact hippocampus and the CA3-lesioned hippocampus at 3 months after administration of kainic acid. Entorhinal axons were visualized by anterograde tracing using injections of the biotinylated dextran amine into the entorhinal cortex. In the CA1 subfield of the intact hippocampus, entorhinal axons were conspicuous in the alveus and the stratum lacunosum moleculare. The distribution in the strata oriens, pyramidale, and radiatum was sparse and was characterized by isolated entorhinal fibers of the alvear pathway crossing these strata to the stratum lacunosum moleculare. However, after kainic acid-induced CA3 lesion, the density of entorhinal axons increased significantly in the CA1 stratum radiatum (375% of the intact hippocampus), as a large number of axons emanating from the entorhinal fiber plexus in the stratum lacunosum moleculare invaded the stratum radiatum. The stratum radiatum also exhibited wavy entorhinal axons filled with boutons and oriented parallel to the stratum pyramidale, suggesting collateral sprouting from entorhinal axons traversing the stratum radiatum. Thus, a significant aberrant sprouting of entorhinal axons occurs into the CA1 stratum radiatum after CA3 lesion. The sprouted fibers appear to come from both entorhinal fiber plexus in the stratum lacunosum moleculare (translaminar sprouting) and entorhinal axons traversing the stratum radiatum (intralaminar sprouting). However, the major contribution appears to be from the entorhinal plexus in the stratum lacunosum moleculare. This aberrant sprouting may lead to altered afferent excitatory connectivity in the CA1 subfield and contribute to the persistent CA1 hyperexcitability that occurs after the CA3 lesion.

Animals↗
PubMed2004

Properties of horizontal axo-axonic cells in stratum oriens of the hippocampal CA1 area of rats in vitro.

Local-circuit gamma-aminobutyric acid (GABA)ergic interneurons constitute a diverse population of cells, which remain poorly defined into functionally distinct subclasses. Traditionally, dendritic and axonal arbors have been used to describe cell classes. In the present report, we characterize a set of hippocampal interneurons, horizontal axo-axonic cells, located in stratum oriens. They displayed the pattern of axonal arborization characteristic of axo-axonic cells with radially aligned rows of boutons making synapses exclusively on axon initial segments of pyramidal cells, as shown by electron microscopy. However, in contrast to previously described axo-axonic cells, which have radial dendrites spanning all layers, the dendrites of the horizontal axo-axonic cells were restricted to stratum oriens and ran parallel with the layers for several hundred micrometers. Single action potentials elicited by depolarizing current steps in these cells were often followed by a fast- and medium-duration afterhyperpolarization, distinguishing them from fast-spiking interneurons. In two out of four cells, trains of action potentials showed prominent early spike frequency adaptation and a characteristic "accommodative hump." Excitatory postsynaptic potentials (EPSPs) could be evoked by stimuli delivered to stratum oriens. Paired recordings unequivocally confirmed direct synaptic inputs from CA1 pyramidal cells. The kinetics of the EPSPs were fast (rise time 1.7 +/- 0.6 ms, mean +/- SD, n = 3; decay time constant 19.3 +/- 2.4 ms). They showed paired-pulse depression with inter-stimulus intervals of 10-50 ms. One pair showed a reciprocal connection establishing a direct feedback loop. The axo-axonic cell-evoked inhibitory postsynaptic potentials (IPSPs) were reliable (failure rate approximately 10%). Our data show that the laminar distribution of the dendrites of axo-axonic cells can vary, suggesting distinct synaptic inputs. However, this remains to be shown directly, and we cannot exclude the possibility that all axo-axonic cells may gather similar synaptic input, leaving them as one distinct class of interneuron.

Action Potentials↗
PubMed1993

Molecular and cellular properties of mammalian primary olfactory axons.

How are the axonal projections of olfactory and vomeronasal receptor neurons to the olfactory bulb formed during development? How are the primary olfactory axonal connections functionally organized? With progress in molecular biological techniques and histochemical methods, it became possible to study cellular strategies and molecular mechanisms which guide the primary olfactory axons of the main and accessory olfactory systems to the target glomeruli in the bulb. In addition, new methodologies have begun to elucidate various subsets of the primary olfactory axons with distinctive central connections. The aim of the present paper is to review (1) the characteristic organization of the projection of the primary olfactory axons, (2) projection patterns of histochemically defined subsets of primary olfactory axons, and (3) information on molecules expressed by the surface membrane of the primary olfactory axons. This knowledge gives insight into the functional organization of the primary olfactory axon projection, which is indispensable for understanding signal processing in the olfactory system. This knowledge also underscores the notion that the primary olfactory axon projection provides an excellent model system in which to study axonal guidance and the formation of specific synaptic connections.

Animals↗
PubMed2004

Dynamics of oligodendrocyte responses to anterograde axonal (Wallerian) and terminal degeneration in normal and TNF-transgenic mice.

The inflammatory cytokine tumour necrosis factor (TNF) can both induce oligodendrocyte and myelin pathology and promote proliferation of oligodendrocyte progenitor cells and remyelination. We have compared the response of the oligodendrocyte lineage to anterograde axonal (Wallerian) and terminal degeneration and lesion-induced axonal sprouting in the hippocampal dentate gyrus in TNF-transgenic mice with the response in genetically normal mice. Transectioning of the entorhino-dentate perforant path axonal projection increased hippocampal TNF mRNA expression in both types of mice, but to significantly larger levels in the TNF-transgenics. At 5 days after axonal transection, numbers of oligodendrocytes and myelin basic protein (MBP) mRNA expression in the denervated dentate gyrus in TNF-transgenic mice had increased to the same extent as in nontransgenic littermates. At this time, transgenics showed a tendency towards a greater increase in the number of juxtaposed, potentially proliferating oligodendrocytes. Noteworthy, at day 5 we also observed upregulation of MBP mRNA expression in adjacent hippocampal subregions with lesion-induced axonal sprouting, which were devoid of axonal degeneration, raising the possibility that sprouting axons provide trophic stimuli to the oligodendrocyte lineage. Twenty-eight days after lesioning, oligodendrocyte numbers and MBP mRNA expression were reduced to near normal levels. However, oligodendrocyte densities in the TNF-transgenic mice were significantly lower than in nontransgenics. We conclude that the early response of the oligodendrocyte lineage to axonal lesioning and lesion-induced axonal sprouting appears unaffected by the supranormal TNF levels in the TNF-transgenic mice. TNF may, however, have long-term inhibitory effects on the oligodendrocyte response to axonal lesioning.

Animals↗
PubMed1990

Damage to bulbospinal serotonin-, tyrosine hydroxylase-, and TRH-containing axons occurs early in the development of experimental allergic encephalomyelitis in rats.

Spinal cord monoaminergic and peptidergic axonal damage occurring during the development of experimental allergic encephalomyelitis (EAE) was assessed using immunohistochemistry. Spinal cord axons immunoreactive for serotonin, catecholamines, or a thyrotropin-releasing hormone marker peptide were found to be markedly swollen and distorted by the earliest stage of detectable paralysis during EAE development (the flaccid tail stage). As clinical signs progressed to complete hindlimb paralysis, axonal damage became increasingly extensive. Axonal damage was equally pronounced whether EAE was induced by inoculation with purified myelin basic protein or with whole spinal cord homogenate, suggesting that the damage did not result from an immune attack directed against specific monoaminergic and/or peptidergic antigens present in the inoculant. However, two observations suggested that mechanical or chemical factors associated with the inflammatory foci contribute to the axonal damage: first, distorted axons were nearly always located adjacent to blood vessels or the pial surface, sites at which inflammation occurs during EAE. Second, the severity of axonal damage correlated with the severity of the inflammation. The early onset of axonal damage during development of EAE and the close correlation that was found between the severity of axonal damage and the severity of clinical signs suggested that the axonal damage may contribute to the clinical signs of the disease.

Animals↗
PubMed2002

Effects of voluntary activity on the excitability of motor axons in the peroneal nerve.

To investigate whether there are inter-nerve differences in the extent and pattern of axonal excitability changes produced by voluntary contractions of tibialis anterior (TA) and abductor pollicis brevis (APB), threshold tracking was used to measure axonal excitability parameters [threshold, supernormality and strength-duration time constant (tauSD)] of peroneal and median motor axons in 11 healthy subjects. Maximal contractions for 1 min resulted in an increase in threshold, an increase in supernormality, a decrease in tauSD and an increase in latency, all of which indicate axonal hyperpolarization. The increase in threshold was less in peroneal axons (18 +/- 4%) than median axons (37 +/- 6%, mean +/- SEM, P < 0.001), and was accompanied by smaller absolute changes in latency, supernormality, and tauSD. Peroneal axons had less supernormality at rest but a greater change in supernormality for the change in threshold. There were major contraction-induced changes in the compound muscle action potential of TA but not that of APB. Voluntary contractions depress axonal excitability, but the changes are quantitatively different for motor axons innervating different muscles. There are three clinical implications. First, weakness and fatigue due to activity-dependent conduction block may vary for different muscles, independent of disease severity, and therapeutic strategies to overcome activity-dependent conduction block may not be equally effective for different muscles. Second, in motor control studies using the H reflex to document motoneuron excitability, a constant stimulus will not produce a constant neural volley if the stimulated axons have been activated by, for example, a voluntary contraction. Third, TA is probably not optimal for testing for activity-dependent conduction block.

Action Potentials↗
PubMed2006

L1, beta1 integrin, and cadherins mediate axonal regeneration in the embryonic spinal cord.

Embryonic birds and mammals are capable of axon regeneration after spinal cord injury, but this ability is lost during a discrete developmental transition. We recently showed that changes within maturing neurons, as opposed to changes solely in the spinal cord environment, significantly restrict axon regeneration during development. The developmental changes within neurons that limit axon regeneration remain unclear. One gap in knowledge is the identity of the adhesive receptors that embryonic neurons use to extend axons in the spinal cord. Here we test the roles of L1/NgCAM, beta1 integrin, and cadherins, using a coculture system in which embryonic chick brainstem neurons regenerate axons into an explant of embryonic spinal cord. By in vivo and in vitro methods, we found that brainstem neurons reduce axonal expression of L1 as they mature. Disrupting either L1 or beta1 integrin function individually in our coculture system partially inhibited growth of brainstem axons in spinal cords, while disrupting cadherin function alone had no effect. However, when all three adhesive receptors were blocked simultaneously, axon growth in the spinal cord was reduced by 90%. Using immunohistochemistry and in situ hybridization we show that during the period when neurons lose their regenerative capacity they reduce expression of mRNA for N-cadherin, and reduce axonal L1/NgCAM protein through a post-transcriptional mechanism. These data show that embryonic neurons use L1/NgCAM, beta1 integrin, and cadherin receptors for axon regeneration in the embryonic spinal cord, and raise the possibility that a reduced expression of these essential receptors may contribute to the low-regenerative capacity of older neurons.

Age Factors↗
PubMed1976

Anatomical basis for an apparent paradox concerning conduction velocities of two identified axons in Aplysia.

Larger axons usually have faster conduction velocities, lower thresholds, and larger extracellular action potentials than smaller axons. However, it has been shown that the largest fiber, R2, in the right pleurovisceral connective of the marine mollusc, Aplysia, has a higher threshold and a slower conduction velocity than does the smaller axon of cell RI, even though the amplitude of R2's spike is larger than R1's spike. One explanation of this apparent parodox is that the two axons have different "intrinsic membrane and axoplasmic constants" (Goldman, L. (1961), J. Cell Comp. Physiol. 57: 185-191). However, the deep infolding of R2's axonal membrane suggested that differences in the shape of the two axons might also account for the paradox. Accordingly, we measured the conduction velocities of the two axons and then examined the same axons in the electron microscope in order to measure their volumes and surface areas. Our morphological observations indicate that the extensive infolding of surface membrane causes R2 to have a smaller volume to surface area ratio than R1. Thus, since conduction velocity is proportional to the square root of the volume to surface area ratio (Hodgkin, A.L. (1954), J. Physiol. 125: 221-224), it is predictable that the smaller axon would have a faster conduction velocity. The results suggest that the paradoxical conduction velocities can be explained largely as resulting from differences in the shapes of the two axons. However, certain discrepancies between the measured and the predicted values suggest that other factors are contributing as well.

Animals↗
PubMed1994

Axonal outgrowth within the abnormal scaffold of brain tracts in a zebrafish mutant.

The role of specific axonal tracts for the guidance of growth cones was investigated by examining axonal outgrowth within the abnormal brain tracts of zebrafish cyclops mutants. Normally, the earliest differentiating neurons in the zebrafish brain establish a simple scaffold of axonal tracts. Later-developing axons follow cell-specific pathways within this axonal scaffold. In cyclops embryos, this scaffold is perturbed due to the deletion of some ventromedial neurons that establish parts of the axonal scaffold and the development of an abnormal crease in the brain. In these mutant embryos, the growth cones projected by the neurons of the nucleus of the posterior commissure (nuc PC) are deprived of the two tracts of axons that they sequentially follow to first extend ventrally, then posteriorly. These growth cones respond to the abnormal scaffold in several interesting ways. First, nuc PC growth cones initially always extend ventrally as in wild-type embryos. This suggests that for the first portion of their pathway the axons they normally follow are not required for proper navigation. Second, approximately half of the nuc PC growth cones follow aberrant longitudinal pathways after the first portion of their pathway. This suggests that for the longitudinal portion of the pathway, specific growth cone/axon interactions are important for guiding growth cones. Third, although approximately half of the nuc PC growth cones follow aberrant longitudinal pathways, the rest follow normal pathways despite the absence of the axons that they normally follow. This suggests that cues independent of these axons may be capable of guiding nuc PC growth cones as well. These results suggest that different guidance cues or combinations of cues guide specific growth cones along different portions of their pathway.

Animals↗
PubMed1994

Growth behavior of retinotectal axons in live zebrafish embryos under TTX-induced neural impulse blockade.

The growth dynamics of individual DiO-labeled retinal axons deprived of normal neural impulse activity by TTX was monitored in the tectum of living zebrafish embryos with time-lapse video microscopy and compared with normal active axons. Growth cones of TTX-blocked axons advance intermittently with an average velocity similar to normal axons. While exploring their local environment, they are broadened and bear ruffling lamellipodia and filopodia, but become streamlined when advancing. The activity-deprived axons grow directly towards their retinotopic target sites in the tectum as do their normal counterparts and very rarely extend branches en route. Much like normal axons, TTX-blocked axons begin to branch and develop their terminal arbors only at their retinotopic target area. They emit and retract numerous short side branches over a period of several hours. The area they contact (the "exploration field") is of similar dimension as that of active axons, covering from 1% to 7.4% of the tectal neuropil surface, but the final arbors cover an area only one-half to one-sixth as large. TTX arbors are as small as arbors of normal active axons and retinotopically correct. Thus, the typical exploratory growth behavior of developing retinal axons in the tectum, the dynamics of terminal arbor formation at retinotopically correct sites, the dimension of the exploration field, and the shaping of the arbors in zebrafish embryos are unaffected by TTX-induced neural impulse blockade.

Animals↗
PubMed1991

Immunocytochemical evidence for methamphetamine-induced serotonergic axon loss in the rat brain.

Central serotonin (5-HT) axons were visualized by immunocytochemistry to assess both acute and long-lasting changes in innervation density following methamphetamine administration to rats. Two morphologically distinct subtypes of 5-HT axons (fine and beaded) were differentially affected by d-methamphetamine (d-MA); the density of fine serotonergic axons was selectively decreased both 4 hours and 2 weeks after administration of d-MA. Acute depletion of 5-HT from fine axons, but not from beaded axons, was observed in the brains of all rats treated 4 hours previously with either a 100 mg/kg or 15 mg/kg dose of d-MA. Persistent loss of 5-HT axons was observed in 30% of rats treated 1 or 2 weeks previously with doses of d-MA which produce long-term deficits in biochemical markers for 5-HT. In the fraction of animals that exhibited denervation, fine serotonergic fibers were selectively ablated by d-MA, but beaded serotonergic fibers were spared. Thus, d-MA is similar to other amphetamine derivatives (e.g., p-chloroamphetamine, 3,4-methylenedioxyamphetamine) in that it acts selectively upon a morphologically distinct class of 5-HT axons but differs in that it produces long-lasting axon loss in only a fraction of animals. These data provide morphologic evidence of 5-HT axon loss following methamphetamine administration and further confirm the differential vulnerability of a particular morphological subtype of serotonergic axons to the neurotoxic effects of substituted amphetamines.

Animals↗
PubMed1997

Mesodermal guidance of pioneer axon growth.

Pioneer axons in insect legs are experimentally accessible model systems for the molecular identification and cellular localization of guidance cues regulating the path of axon growth. A detailed study of the Fe2 pioneer axons in the legs of the cockroach was performed to examine the diversity of guidance mechanisms. A detailed microscopic analysis of the axons at various points in their trajectory indicates that the Fe2 axons grow on a mesodermal substratum which contains the cues guiding their growth along a stereotyped path. An identified pair of muscle pioneer cells (MPC) are likely to play an important role in enabling the Fe2 growth cones to respond to mesodermal guidance cues. The addition of heparan sulfate, heparitinase, and phosphatidylinositol-specific phospholipase C to the medium perturbs the in situ path of growth of the Fe2 axons and the location of the MPC in cultured embryos. This indicates a role for heparan sulfate proteoglycans and glycosylphosphatidylinositol-anchored proteins in axon guidance. When these results are compared to those of similar experiments performed on the well-characterized Ti1 axons, they indicate significant differences in the mechanisms that are used for axon guidance. The Fe2 neurons are a good model for elucidating the mechanisms used to guide axon growth on nonmuscle mesodermal substrates often encountered in the periphery of vertebrate embryos.

Animals↗
PubMed2000

DCC plays a role in navigation of forebrain axons across the ventral midbrain commissure in embryonic xenopus.

In the developing vertebrate brain, growing axons establish a scaffold of axon tracts connected across the midline via commissures. We have previously identified a population of telencephalic neurons that express NOC-2, a novel glycoform of the neural cell adhesion molecule N-CAM that is involved in axon guidance in the forebrain. These axons arise from the presumptive telencephalic nucleus, course caudally along the principal longitudinal tract of the forebrain, cross the ventral midline in the midbrain, and then project to the contralateral side of the brain. In the present study we have investigated mechanisms controlling the growth of these axons across the ventral midline of the midbrain. The axon guidance receptor DCC is expressed by the NOC-2 population of axons both within the longitudinal tract and within the ventral midbrain commissure. Disruption of DCC-dependent interactions, both in vitro and in vivo, inhibited the NOC-2 axons from crossing the ventral midbrain. Instead, these axons grew along aberrant trajectories away from the midline, suggesting that DCC-dependent interactions are important for overcoming inhibitory mechanisms within the midbrain of the embryonic vertebrate brain. Thus, coordinated responsiveness of forebrain axons to both chemostimulatory and chemorepulsive cues appears to determine whether they cross the ventral midline in the midbrain.

Animals↗
PubMed1997

Effects of extracellular matrix components on axonal outgrowth from peripheral nerves of adult animals in vitro.

Relatively little is known of the growth requirements for regenerating axons of the peripheral nervous system of adult animals. In the present study, we show that extracellular matrix material secreted by the Engelbreth-Holm-Swarm tumor cell line (matrigel) supports axonal growth from explanted peripheral nerve-dorsal root ganglia (DRG) preparations of adult mice and amphibia in serum-free media, without addition of growth factors. Axonal growth in matrigel was much more profuse than that in the more commonly used gels of type 1 collagen and, after some days in culture, was accompanied by migration of Schwann cells along axons. The most abundant protein in matrigel is laminin, which has been shown in many studies to support axonal growth but, surprisingly, antisera to laminin did not inhibit axonal growth in matrigel. To determine the ability of the major components of matrigel, laminin, type IV collagen, and heparan sulfate proteoglycan (HSPG), to support axonal growth, these proteins were added to preparations of mouse peripheral nerve-DRGs in type I collagen gels. Regenerating axons were significantly longer in the presence of laminin and type IV collagen than in control cultures, while HSPG had a slight inhibitory effect. In this assay system, however, diluted matrigel solution was even more effective in stimulating axonal growth than laminin or type IV collagen, either alone or in combination. The results suggest that in addition to laminin and type IV collagen, other components within matrigel may contribute to its ability to support axonal growth.

Ambystoma mexicanum↗
PubMed1998

Selective inhibition of early axonal regeneration by myelin-associated glycoprotein.

When the distal stump of a transected peripheral nerve is brought into the vicinity of the proximal nerve stump, the regenerating axons advance toward it across the gap. Similar results are obtained when a predegenerated nerve segment is used. However, when a nerve segment subjected to proximal axotomy 7 days earlier (7-day nerve segment) was placed close to the proximal end of a freshly cut nerve at a distance of less than 1.5 mm, there were neither regenerating axons nor sprouts. The same inhibition of axonal regeneration was also exhibited when a nerve segment subjected to axotomy 9 to 14 days earlier was used. To examine the inhibitory effect of the nerve segments on established regenerating axons, we positioned a 7-day nerve segment in close apposition to a proximal nerve end at 2 or 3 days after transection. The growth of the 3-day-old regenerating axons, already ensheathed by Schwann cells, was not disturbed, but the 2-day-old regenerating axons, consisting of naked axons, were eliminated by the 7-day nerve segment. It is assumed that the findings reflect a mechanism serving to eliminate abundant sprouts and immature axons, probably conferring optimum regeneration and maturation of outgrowing pioneer axons. The inhibitory effect on abundant sprouts and immature axons was completely blocked by local application of antibodies to myelin-associated glycoprotein (MAG). The MAG-containing cells appeared at 6 to 12 days after axotomy.

Animals↗
PubMed1998

A quantifiable model of axonal regeneration in the demyelinated adult rat spinal cord.

Strategies to increase the extent of axonal regeneration in the adult CNS must address an array of intrinsic and environmental factors which influence neuritic outgrowth. In order to develop an in vivo model of axonal regeneration in which potential therapies may be assessed, we have quantified growth cones within demyelinated regions in the dorsal funiculus of the spinal cord, following a discrete axotomy. Demyelinated lesions were produced by the intraspinal injection of galactocerebroside antibodies plus serum complement proteins. Axonal integrity was not compromised by the demyelination protocol. Axonal injury was induced at the caudal extent of the demyelinated region using a micromanipulator-controlled Scouten knife. The severity of axonal injury was varied in different animals at the time of surgery and was quantified 8 days later by counting degenerate axons in transverse 1-microm resin sections. Evidence of axonal regeneration within these animals was assessed by an electron microscopic analysis of growth cone frequency and position relative to the site of axotomy. Growth cones were identified within the region of demyelination only; no growth cones were identified within the dorsal column white matter adjacent to the demyelinated region, or rostral or caudal to the region of demyelination, or in animals with an injury but no demyelination. Quantification of growth cones within regions of demyelination indicated a strong linear relationship (P < 0.001) between the number of growth cones and the number of axons severed. These findings indicate that demyelination facilitates axonal regeneration in the adult rat CNS and illustrate a quantifiable method of assessing axonal regeneration.

Age Factors↗
PubMed2002

Transplants of fibroblasts genetically modified to express BDNF promote axonal regeneration from supraspinal neurons following chronic spinal cord injury.

Transplants of fibroblasts genetically modified to express BDNF (Fb/BDNF) have been shown to promote regeneration of rubrospinal axons and recovery of forelimb function when placed acutely into the injured cervical spinal cord of adult rats. Here we investigated whether Fb/BDNF cells could stimulate supraspinal axon regeneration and recovery after chronic (4 week) injury. Adult female Sprague-Dawley rats received a complete unilateral hemisection injury at the third cervical spinal cord segment (C3). Four-five weeks later the injury site was exposed and rats received transplants of unmodified fibroblasts (Fb/UM) or Fb/BDNF. Four-five weeks after transplantation, locomotor recovery was examined on a test of forelimb usage and regeneration of supraspinal axons was studied following injection of the anterograde tracer biotin dextran amine (BDA). Rubrospinal tract (RST), reticulospinal tract (ReST), and vestibulospinal tract (VST) axons regenerated into transplants of either Fb/UM or Fb/BDNF but the length of axonal growth was significantly different in the two groups. The absolute distance of ReST growth was 1.8-fold greater in Fb/BDNF than in Fb/UM and the absolute distance of growth of RST and VST axons showed a statistically significant 4-fold increase. All three types of regenerated axons occupied a greater proportional length of Fb/BDNF transplants than of Fb/UM transplants. Only VST axons extended into the host spinal cord caudal to the Fb/BDNF grafts, but these axons were sparse. Rats receiving Fb/BDNF used both forelimbs together to explore walls of a cylinder more often than rats receiving Fb/UM, indicating partial recovery of forelimb usage. These results demonstrate that fibroblasts genetically modified to express BDNF promote axon regeneration from supraspinal neurons in the chronically injured spinal cord with accompanying partial recovery of locomotor performance.

Animals↗
PubMed1998

Many major CNS axon projections develop normally in the absence of semaphorin III.

The semaphorins constitute a large gene family of transmembrane and secreted molecules, many of which are expressed in the nervous system. Genetic studies in Drosophila have revealed a role for semaphorins in axon guidance and synapse formation, and several in vitro studies in mice have demonstrated a dramatic chemorepellent effect of semaphorin III (Sema III) on the axons of several populations of neurons. To investigate the function of Sema III during in vivo axon guidance in the mammalian CNS, we studied the development of axonal projections in mutant mice lacking Sema III. Projections were studied for which either the in vitro evidence suggests a role for Sema III in axon guidance (e.g., cerebellar mossy fibers, thalamocortical axons, or cranial motor neurons) or the in vivo expression suggests a role for Sema III in axon guidance (e.g., cerebellar Purkinje cells, neocortex). We find that many major axonal projections, including climbing fiber, mossy fiber, thalamocortical, and basal forebrain projections and cranial nerves, develop normally in the absence of Sema III. Despite its in vitro function and in vivo expression, it appears as if Sema III is not absolutely required for the formation of many major CNS tracts. Such data are consistent with recent models suggesting that axon guidance is controlled by a balance of forces resulting from multiple guidance cues. Our data lead us to suggest that if Sema III functions in part to guide the formation of major axonal projections, then it does so in combination with both other semaphorins and other families of guidance molecules.

Animals↗