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PubMed1979

Extra-axonal diffusion in the rabbit optic system: a caution in axonal transport studies.

The hazards of using optic nerve (as opposed to optic tract and more distal components of the optic system) to study axonal transport were highlighted by observing the fate of [14C]serine and [3H]glycerol injected into the rabbit eye. Despite prior blockage of axonal transport with colchicine, appreciable radioactivity rapidly appeared in the optic nerve adjacent to the injected eye. Radioactivity decreased exponentially along the entire optic chiasm. Counts were distributed among the lipid, protein, and acid-soluble fractions. Separation of optic nerve lipids revealed appreciable labeling of most lipid classes including those characteristic of myelin; a markedly different labeling pattern was observed for axonally transported lipids. The data are consistent with a mechanism involving extra-axonal diffusion of precursor into the surrounding glia followed by incorporation into lipids and proteins of those cells and ultimately myelin. The phenomenon is discussed in relation to possible errors that were made in interpreting earlier experiments.

Animals↗
PubMed1982

Redistribution of proteins of fast axonal transport following administration of beta,beta'-iminodipropionitrile: a quantitative autoradiographic study.

Beta,beta'-iminodipropionitrile (IDPN) produces a rearrangement of axoplasmic organelles with displacement of microtubules, smooth endoplasmic reticulum, and mitochondria toward the center and of neurofilaments toward the periphery of the axon, whereas the rate of the fast component of axonal transport is unchanged. Separation of microtubules and neurofilaments makes the IDPN axons an excellent model for study of the role of these two organelles in axonal transport. The cross-sectional distribution of [3H]-labeled proteins moving with the front of the fast transport was analyzed by quantitative electron microscopic autoradiography in sciatic nerves of IDPN-treated and control rats, 6 h after injection of a 1:1 mixture of [3H]-proline and [3H]-lysine into lumbar ventral horns. In IDPN axons most of the transported [3H] proteins were located in the central region with microtubules, smooth endoplasmic reticulum and mitochondria, whereas few or none were in the periphery with neurofilaments. In control axons the [3H]-labeled proteins were uniformly distributed within the axoplasm. It is concluded that in fast axonal transport: (a) neurofilaments play no primary role; (b) the normal architecture of the axonal cytoskeleton and the normal cross-sectional distribution of transported materials are not indispensable for the maintenance of a normal rate of transport. The present findings are consistent with the models of fast transport that envision microtubules as the key organelles in providing directionality and propulsive force to the fast component of axonal transport.

Animals↗
PubMed1981

Axonal transport maintains taste responses.

Transection of the gerbil's IXth nerve causes gustatory action potentials to decline in 1-6 h; the rate of decline is a linear function of the length of the nerve stump remaining attached to the tongue. To test the implication that taste discharge mechanisms depend upon axonal transport in the IXth nerve, we injected 40 nl of [3H]leucine into the petrosal ganglion of one IXth nerve of the gerbil, Meriones unguiculatus. Subsequent liquid scintillation counting of the petrosal ganglion, IXth nerve segments, and representative areas of the tongue indicated that labeled materials were transported down the IXth nerve primarily to the vallate and ipsilateral foliate taste papillae of the tongue. A significant impairment of axonal transport and a substantial decline in summated IXth nerve taste responses occurred within 2-3 h after colchicine was applied to the IXth nerve trunk between the tongue and the petrosal ganglion. Similarly, cooling the IXth nerve with a 3-10 degrees C thermocouple junction or metal probe impaired axonal transport and caused a taste response decline. Since impulse mechanisms of the nerve trunk continued to function distal to these sites of treatment, we concluded that the maintenance of taste discharges at the level of the taste bud depends upon unimpeded axonal transport.

Action Potentials↗
PubMed1981

Axonal transport: a quantitative study of retained and transported protein fraction in the cat.

The fast axonal transport of proteins was studied in the cat sciatic nerve after injection of [3H]leucine into the spinal ganglion or the ventral horn of the seventh lumbar segment. The amount of transported proteins after ganglion injection was linearly related to the amount of label present at the ganglion. At variable intervals after ganglion or spinal cord injection, the sciatic nerves were sectioned in some experiments. The transport of proteins continued in the peripheral nerve stump in a wavelike manner, but the advancing wave leaves a labeled trail behind. A fraction of this trail corresponds to proteins moving at slower velocities than the velocity of proteins in the wave front. Another fraction of the trail corresponds to molecules retained by the axons. Each nerve segment of 5 mm in length retains 1.5% of the transported proteins, and the profile of retained proteins along the sciatic nerves follows a single exponential function. From the proportion of retained proteins, the concentration of transported proteins at the terminals of branching axons as a function of the branching ratio was estimated. In the case of motor axons innervating the soleus muscle of the cat, the concentration of recently transported proteins at the nerve terminals would be approximately 0.83% of the proteins leaving the spinal cord. This low concentration of transported proteins at the nerve terminals may explain the lability of neuromuscular synapses when axonal transport is decreased or interrupted.

Animals↗
PubMed1992

Actin depolymerizing factor is a component of slow axonal transport.

We examined the low molecular weight proteins transported with actin in the chicken sciatic nerve after injection of [35S]methionine into the lumbar spinal cord. A prominent component of slow axonal transport with apparent molecular mass 19 kDa comigrated on two-dimensional gels with chicken actin depolymerizing factor (ADF), previously shown to be a major actin-binding protein in brain. There was comparatively little radioactivity associated with the actin monomer sequestering proteins, profilin or cofilin, and examination of the rapid component of axonal transport failed to reveal appreciable quantities of actin, ADF, profilin, or cofilin. These results show that both actin and ADF are carried by slow axonal transport and raise the possibility that actin travels within the axon in an unpolymerized form in a complex with ADF.

Actin Depolymerizing Factors↗
PubMed1981

Protein synthesis and axonal transport during nerve regeneration.

Protein synthesis and axonal transport have been studied in regenerating peripheral nerves. Sciatic nerves of bullfrogs were unilaterally crushed or cut. The animals were killed 1, 2, or 4 weeks later, and 8th and 9th dorsal root ganglia removed together with sciatic nerves and dorsal roots. The ganglia were selectively labeled in vitro with [35S]-methionine. Labeled proteins, in dorsal root ganglia and rapidly transported to ligatures placed on the sciatic nerves and dorsal roots, were analyzed by two-dimensional polyacrylamide gel electrophoresis. Qualitative analysis of protein patterns revealed no totally new proteins synthesized or rapidly transported in regenerating nerves. However, quantitative comparison of regenerating and contralateral control nerves revealed significant differences in abundance for some of the proteins synthesized in dorsal root ganglia, and for a few of the rapidly transported proteins. Quantitative analysis of rapidly transported proteins in both the peripheral processes (spinal nerves) and central processes (dorsal roots) revealed similar changes despite the fact that the roots were undamaged. The overall lack of drastic changes seen in protein synthesis and transport suggests that the neuron in its program of normal maintenance synthesizes and supplies most of the materials required for axon regrowth.

Animals↗
PubMed1984

[Composition of the polypeptides participating in orthograde axonal transport in the nerve elements of the caudal mesenteric ganglion of the cat].

Composition of the polypeptides translocated by the axonal transport in the lumbar splanchnic and hypogastric nerves before and after total section of these nerves was studied in the model of the inferior mesenteric ganglion with pre- and postganglionic nerve trunks. The data obtained suggest presence of the orthograde axonal transport of specific proteins associated with the nerve fibre growth along the axons of afferent neurons whose bodies are localized in the inferior mesenteric ganglion, as well as along efferent fibres with trophic centers situated in the ganglion. Axonal transport of the polypeptide with molecular weight 29.000 Dalton unidentified in other nerve structures was shown to occur along the afferent fibers.

Animals↗
PubMed1980

Optic nerve fast axonal transport abnormalities in primates. Occurrence after short posterior ciliary artery occlusion.

Fast axonal transport abnormalities in primate (Aotus trivirgatus) optic nerve were studied in ten eyes at various intervals after occlusion of the lateral short posterior ciliary circulation. Evidence of focal axonal ischemia, as indicated by swelling of mitochondria and dissolution of cytoplasmic detail, was noted as early as one hour after occlusion. Accumulation of mitochondria, microvesicles, and dense bodies, indicating focal interruption of axonal transport mechanisms, was noted in eyes examined at 2, 4, and 6 hours. This accumulation of organelles was limited to the region of the lamina cribrosa. Nerve head abnormalities were not seen in two eyes studied at two weeks.

Animals↗
PubMed1990

A monoclonal antibody against kinesin inhibits both anterograde and retrograde fast axonal transport in squid axoplasm.

One of our monoclonal antibodies against the heavy chain of bovine kinesin (H2) also recognized the heavy chain of squid kinesin. The immunofluorescence pattern of H2 in axoplasm was similar to that seen in mammalian cells with antibodies specific for kinesin light and heavy chains, indicating that squid kinesin is also concentrated on membrane-bounded organelles. Although kinesin is assumed to be a motor for translocation of membrane-bounded organelles in fast axonal transport, direct evidence has been lacking. Perfusion of axoplasm with purified H2 at 0.1-0.4 mg/ml resulted in a profound inhibition of both the rates and number of organelles moving in anterograde and retrograde directions in the interior of the axoplasm, and comparable inhibition was noted in bidirectional movement along individual microtubules at the periphery. Maximal inhibition developed over 30-60 min. Perfusion with higher concentrations of H2 (greater than 1 mg of IgG per ml) were less effective, whereas perfusion with 0.04 mg of H2 per ml resulted in minimal inhibition. Movement of membrane-bounded organelles after perfusion with comparable levels of irrelevant mouse IgG (0.04 to greater than 1 mg/ml) were not distinguishable from perfusion with buffer controls. Inhibition of fast axonal transport by an antibody specific for kinesin provides direct evidence that kinesin is involved in the translocation of membrane-bounded organelles in axons. Moreover, the inhibition of bidirectional axonal transport by H2 raises the possibility that kinesin may play some role in both anterograde and retrograde axonal transport.

Adenosine Triphosphatases↗
PubMed1979

[Application to the study of connections in the CNS of the retrograde axonal transport of an iron-dextran complex].

The retrograde axonal transport of an iron-dextran complex was observed in neurons of the substantia nigra and of the intralaminar nuclei of the thalamus, after previous injection into the striatum. The histochemical demonstration of iron is simple and rapid, and can be combined with that of horseradish peroxidase, under precise conditions in the sequence of reactions. The iron-dextran complex revealed to be a valuable material for neuronal connectivity studies in the central nervous system.

Animals↗
PubMed1996

The axonal transport of beta III-tubulin is altered in both branches of sensory axons after injury of the rat sciatic nerve.

We have analyzed the axonal transport of beta III-tubulin in the central (dorsal root) and peripheral (sciatic nerve) branches of sensory axons after injury of the sciatic nerve. Our finding that the relative amount of beta III-tubulin transported in slow component b (SCb) is increased in both axonal branches does not support the generally accepted hypothesis that the transport of cytoskeletal proteins is altered in the peripheral, but not the central branch after injury of the sciatic nerve.

Animals↗
PubMed1995

Fast axonal transport of kinesin in the rat visual system: functionality of kinesin heavy chain isoforms.

The mechanochemical ATPase kinesin is thought to move membrane-bounded organelles along microtubules in fast axonal transport. However, fast transport includes several classes of organelles moving at rates that differ by an order of magnitude. Further, the fact that cytoplasmic forms of kinesin exist suggests that kinesins might move cytoplasmic structures such as the cytoskeleton. To define cellular roles for kinesin, the axonal transport of kinesin was characterized. Retinal proteins were pulse-labeled, and movement of radiolabeled kinesin through optic nerve and tract into the terminals was monitored by immunoprecipitation. Heavy and light chains of kinesin appeared in nerve and tract at times consistent with fast transport. Little or no kinesin moved with slow axonal transport indicating that effectively all axonal kinesin is associated with membranous organelles. Both kinesin heavy chain molecular weight variants of 130,000 and 124,000 M(r) (KHC-A and KHC-B) moved in fast anterograde transport, but KHC-A moved at 5-6 times the rate of KHC-B. KHC-A cotransported with the synaptic vesicle marker synaptophysin, while a portion of KHC-B cotransported with the mitochondrial marker hexokinase. These results suggest that KHC-A is enriched on small tubulovesicular structures like synaptic vesicles and that at least one form of KHC-B is predominantly on mitochondria. Biochemical specialization may target kinesins to appropriate organelles and facilitate differential regulation of transport.

Animals↗
PubMed1999

Pig splenic nerve: peptides derived from chromogranins by proteolytic processing during axonal transport.

We have investigated the proteolytic processing of chromogranin A, chromogranin B and NESP55 (a novel chromogranin-like protein) during axonal transport using pig splenic nerve as a model. We have also studied the presence of chromogranin-derived peptides in the perfusate during electrical stimulation of this nerve. High-performance gel filtration chromatography followed by radioimmunoassay (RIA) revealed that chromogranins are proteolytically processed to varying degrees during axonal transport. For chromogranin A and NESP55, the precursor is still present in the proximal part of the nerve, whereas in the distal part and nerve terminals, intermediate-sized peptides and the free peptides GE-25 and GAIPIRRH dominate, respectively. For chromogranin B, the precursor has already been processed to an intermediate-sized peptide in the proximal part of the nerve, which is also present in the distal parts together with the free peptide PE-11. For chromogranin B and NESP55, only the free peptides PE-11 and GAIPIRRH, or in the case of chromogranin A, the free peptide GE-25 plus an intermediate-sized one, are released from the terminals into the splenic perfusate. These results demonstrate that chromogranins are processed to smaller peptides during axonal transport.

Animals↗
PubMed1984

In vivo biosynthesis of [35S]- and [3H]substance P in the striatum of the rat and their axonal transport to the substantia nigra.

The biosynthesis and axonal transport of the neuropeptide substance P (SP) in the striatonigral tract of the rat was examined using an in vivo radiolabeling of the rostral corpus striatum and a series of high performance liquid chromatography (HPLC) steps for the purification of radiolabeled SP. The corpus striatum of unrestrained rats was continuously infused via indwelling cannulae for 16 hr with [35S]methionine or a mix of [3H]leucine and [3H]proline. Radiolabeled SP was acid extracted from discrete regions of this striatonigral SP projection--corpus striatum (SP-immunopositive cell bodies), ansa lenticularis (striatonigral SP axons), and substantia nigra (striatonigral SP terminals)--and was purified to a constant specific activity by sequential HPLC. The radiochemical purity of SP was verified by chemical derivative formation (SP-Met11-sulfoxide) and further HPLC. The in vivo labeling procedure resulted in a high level of incorporation of the amino acids into tissue protein and peptide pools. [35S]SP and [3H]SP were positively identified in all three regions of this peptidergic projection. The amount of [35S]SP harvested in each region accounted for 0.0015%, 0.003%, and 0.071% of the total tissue 35S present in the striatum, striatonigral fibers, and substantia nigra, respectively. The amount of [3H]SP harvested in each region accounted for 0.0025%, 0.011%, and 0.27% of the total tissue 3H present in the three regions, respectively. The amount of radiolabeled SP in the striatonigral regions for both isotopic infusion studies was highly correlated with the immunoassayable SP content in those regions, suggesting rapid equilibration of de novo biosynthesized SP with striatonigral tissue pools of SP. Tritium autoradiography of the striatonigral projection after 3H-amino acid infusion provided further support for the specificity of the radiolabeling procedures. Heavily labeled fibers were seen leaving the striatal infusion site caudally, forming a distinct fiber bundle. This bundle projected caudoventrally and formed a dense terminal plexus primarily within the reticulata portion of the substantia nigra. These results demonstrate that SP biosynthesis in the corpus striatum and its transport to the substantia nigra can be studied in discrete striatonigral regions obtained from individual unrestrained rats. This preparation should allow for studies on the dynamics of SP biosynthesis, axonal transport, and turnover in the striatonigral projection.

Animals↗
PubMed1989

Co-release of neuropeptide Y and noradrenaline from pig spleen in vivo: importance of subcellular storage, nerve impulse frequency and pattern, feedback regulation and resupply by axonal transport.

The importance of subcellular storage, nerve impulse rate and pattern, and feedback regulation, as well as resupply by axonal transport for the release of noradrenaline and neuropeptide Y-like immunoreactivity, was studied in the blood perfused pig spleen in vivo. Vasoconstrictor responses were recorded as perfusion pressure changes. Subcellular fractionation experiments using sucrose density gradients showed a bimodal distribution of noradrenaline (peak concentrations at 0.8 and 1.1 M sucrose) while only one main peak of neuropeptide Y was present (at 1.1 M sucrose). Overflow suggesting release of noradrenaline and neuropeptide Y-like immunoreactivity could be detected after 10 s stimulation at 10 Hz. The ratio for the output of noradrenaline and neuropeptide Y upon continuous nerve stimulation in control animals decreased with frequency. After inhibition of noradrenaline reuptake by desipramine the vasoconstrictor response and noradrenaline output were enhanced while the corresponding overflow of neuropeptide Y was reduced by 50% at 0.5 Hz. Stimulation with the irregular or regular bursting patterns at high frequencies caused larger perfusion pressure increase and relative enhancement of neuropeptide Y output compared to noradrenaline than a continuous stimulation both before and after desipramine treatment. A similar fractional release per nerve impulse was calculated both for [3H]noradrenaline (5.6 +/- 1.0 x 10(-5) and neuropeptide Y (7.3 +/- 0.3 x 10(-5). After reserpine treatment combined with preganglionic denervation the vasoconstrictor responses were more long-lasting, neuropeptide Y release was enhanced while noradrenaline content and release were reduced by 99%. The difference in neuropeptide Y overflow between continuous and bursting types of stimulation was smaller after reserpine treatment. After prolonged intermittent stimulation with regular bursts (20 Hz) for 1 h the splenic content of neuropeptide Y was reduced by 58%, while no change was observed for noradrenaline. The maximal perfusion pressure increase upon prolonged nerve stimulation after reserpine was similar in control and reserpine-treated animals, but after reserpine the vasoconstrictor response and neuropeptide Y release were subjected to fatigue. Ligation experiments of the splenic nerves revealed the splenic neuropeptide Y content was resupplied by axonal transport with a calculated total tissue turnover time of 11 days. In contrast, axonal transport contributed only to a marginal extent for the resupply of noradrenaline.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗
PubMed1987

Optic nerve head axonal transport in rabbits with hereditary glaucoma.

Rabbits with hereditary glaucoma develop ocular changes that resemble human congenital glaucoma and buphthalmia. The inheritance is autosomal recessive (bu). Previous research was performed primarily on albino bu/bu rabbits that were unhealthy and bred poorly. We have bred pigmented bu/bu rabbits to determine if this would improve hardiness and provide a better model for the disease in humans. First-generation offspring from matings of bu/bu albino with bu/bu pigmented rabbits were all affected, indicating that the bu gene is found at the same locus in both strains. The pigmented bu/bu offspring had a high degree of mortality, as reported previously for albino bu/bu rabbits. Newborn bu/bu rabbits initially had normal intraocular pressure (IOP; 15-23 mmHg); after 1- to 3 months, the IOP increased to 26-48 mmHg. The eyes became buphthalmic and the IOP returned to normal or sub-normal levels after 6-10 months. Since the lamina cribrosa is absent or poorly formed in the rabbit optic nerve head (ONH), this model was used to test the role of mechanical factors in the etiology of ONH pathology caused by increased IOP. Orthograde axonal transport was evaluated in both eyes from eight normal and 24 bu/bu rabbits of different ages, using intravitreal injections of [3H]leucine to mark orthograde axonal transport, followed by light- and electron-microscopic radioautography of the ONHs and superior colliculi. Normal rabbits of all ages showed no blockage of axonal transport in the ONH. All optic axons from young bu/bu rabbits with normal IOP and most axons from older buphthalmic rabbits that previously had elevated IOP were normal morphologically. Small zones of transport blockage occurred in bu/bu eyes while IOP was elevated; most affected axons lay immediately adjacent to ONH connective tissue beams that radiate outward from the central retinal vessels to the optic-nerve sheath. Thus, the rabbit, which lacks a true lamina cribrosa, does not show marked blockage of axonal transport as occurs in the LS of the monkey and cat ONH when IOP is elevated acutely. This anatomic difference appears to be protective against axonal damage, since bu/bu rabbits with chronic IOP elevation did not show significant loss of optic axons. These results are consistent with the proposed 'mechanical' theory of ONH damage resulting from increased IOP. Electron-microscopic radioautography revealed that chronically elevated IOP in bu/bu rabbits, which caused small foci of blocked ONH axonal transport against ONH beams, also caused degeneration of a few optic nerve terminals in the superior colliculi as the disease progressed.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗
PubMed1975

Comparison between the effect of colchicine and lumicolchicine on axonal transport in rat motor neurons.

The mitotic inhibitor colchicine (COL) and its isomer lumi-colchicine (lumi-COL) were tested on the axonal transport of acetylcholine (ACh), cholineacetyltransferase (CAT) and ACh-esterase (AChE) in rat motor nerves in vivo. COL was found to be far more effective in blocking axonal transport of all 3 substances than was an equimolar concentration (0.1 M) of lumi-COL, when injected into the sciatic nerve. Since COL and lumi-COL have similar properties as regards binding to cellular membranes, but differ markedly in their binding capacity to microtubule protein, the results give strong support for the theory that microtubules are essential for intra-axonal transport in mammalian nerves.

Acetylcholine↗
PubMed1978

The influence of supraspinal impulse activity on the intra-axonal transport of acetylcholine, choline acetyltransferase and acetylcholinesterase in rat motor neurons.

The effect of supraspinal impulse activity upon the intra-axonal transport of acetylcholine (ACh), ACh esterase (AChE) and cholineacetyltransferase (CAT) in rat sciatic nerve has been studied. A decreased inpulse activity was obtained by spinal cord transsection (SCT) in the thoracic region 18 h, 6 days or 20 days before killing the rats. An increased neuronal activity was obtained by exercising the rats in a commercial rodent treadmill a couple of hours per day for 14 days. The amounts of substances which had accumulated in the sciatic nerve segments relative to a nerve crush performed 12 or 18 h. earlier were used to calculate the intra-axonal transport. The amounts of proximo-distal transported ACh decreased markedly with time after the SCT, while the proximo-distal transport of AChE-activity increased. Physical exercise appeared to increase ACh-transport. Thus, input to motor pericarya from supraspinal centers may regulate intra-axonal transport from the cell body of motor neurons into their axons.

Acetylcholine↗