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Retinal ganglion cells are the output cells of the retina whose axons are under considerable metabolic stress in both health and disease states. They are highly polarised to ensure that mitochondria and enzymes involved in the generation of ATP are strategically concentrated to meet the local energy demands of the cell. In passing from the eye to the brain, axons are protected and supported by glial tissues and the blood supply of the optic nerve head is regulated to maintain the supply of oxygen and nutrients to the axons. In spite of this, the optic nerve head remains the point at which retinal ganglion cell axons are most vulnerable to the effects of increased intraocular pressure or ischaemia. Considerable work has been undertaken in this area to advance our understanding on the pathophysiology of axon damage and to develop new strategies for the prevention of retinal ganglion cell death.
In neurons, tubulin is synthesized only in the cell body or dendrites, yet the growing axon requires a steady supply of this protein at the growth cone. Hence, some mechanism must exist to move tubulin from the cell body to the growth cone. Transport could conceivably occur by simple diffusion, translocation of polymer, or some form of monomer or oligomer transport. Evidence for all these has been presented in a variety of experimental systems. We have directly studied the movement of microtubules in 12 growing axons in live grasshopper Ti1 neurons in their natural environment by labeling the polymer with a caged fluorophore, biscaged fluorescein. No evidence of polymer transport was found. Hence, tubulin movement in these neurons must occur by movement of monomeric tubulin, either by transport or diffusion. To resolve these conflicting views, we discuss the conditions under which diffusion is feasible as a transport mechanism.
Dopamine-beta-hydroxylase activity accumulated above a ligature on biopsy samples of normal human sural nerves incubated in vitro. The rate of accumulation indicated that this enzyme was transported distally at a velocity of 2 millimeters per hour. Axoplasmic transport of dopamine-beta-hydroxylase was greatly reduced in sural nerves from a few patients with peripheral neuropathies.
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Labeling of goldfish optic nerve and tectum proteoglycans (PGs) was quantified following intraocular injection of 35SO4 and [3H]proline or [3H]glucosamine. Both intact animals and animals which had survived for periods of 10 to 119 days after an optic nerve crush lesion were examined. Regenerating retinal ganglion cell (RGC) axons reached the rostral pole of the tectum by 10 days postcrush and by 21 days had densely innervated the optic synaptic laminae. If the contralateral tectum had been removed, the regenerating RGC axons innervated the remaining ipsilateral tectum with a delay of approximately 14 days. There was a biphasic increase in the synthesis and transport of PGs during optic fiber regeneration which was not affected by the removal of the tectum. More highly sulfated PGs were preferentially off-loaded from the orthograde transport pool proximally in the optic nerve, both in the unoperated animals and during regeneration. These PGs also had longer and/or more glycosaminoglycan (GAG) chains than those off-loaded distally, in the tectum. During early regeneration, the synthesis and transport of chondroitin sulfate PGs (CSPGs) increased more than those of heparan sulfate PGs, and during the period of optic fiber invasion of the synaptic laminae, the PGs retained in the nerve had a higher content of CSPGs than those transported into the tectum. Removal of the contralateral tectum at the time of nerve crush resulted in a decrease in the size and/or numbers of GAGs and overall sulfation of PGs in the nerve by 21 days postoperatively.(ABSTRACT TRUNCATED AT 250 WORDS)
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[3H]leucine was injected into the nodose ganglion of the rabbit following ipsilateral supranodose vagotomy to eliminate the vagal efferent fibers. Labeled materials were transported in afferent fibers of the vagus nerve at fast transport rates of 12 cm/day and slow transport of 3-5 cm/day. In particular, axoplasm protein occupied about 40% of the highly labeled component of the slow transport, and the rate of this component was 1.8-2.5 cm/day. It was assumed that the highly labeled component was transported to the diaphragm region within at least 8 days and to the gastrointestinal region within 10 days.
Twenty-two-day-old rats were injected intraocularly with [3H]acetate and killed between 1 hr and 35 days later. Cholesterol was isolated from the retinas, optic tracts, lateral geniculate bodies, and superior colliculi. Within the retina, radioactivity was rapidly incorporated into cholesterol with maximal labeling present one hour after injection. Transported labeled cholesterol (contralaterally corrected for systemic background labeling) was present in the superior colliculus by three hours. Radioactive cholesterol accumulated in all visual structures throughout the 35-day period, but the rate of accumulation was maximal at about the time of arrival of the initial pulse of radioactivity. Colchicine treatment of the retina blocked transport of cholesterol but not its synthesis by the retina. The results indicate that cholesterol is rapidly transported in the visual system and also released from the retina for a prolonged period after its synthesis.
The hypothesis on transmitter specific, retrograde labeling of neuronal pathways and observations relevant to this hypothesis are discussed. After injection of (3H)-glycine into the pigeon optic tectum fast labeling of intrinsic elements in a restricted part of the subtectal n. isthmi, pars parvocellularis (Ipc), is found - strongly suggesting a rapid retrograde migration of radioactivity in neurons of the glycinergic Ipc-tectal pathway. Labeling of neuronal perikarya in the substantia nigra, in cell groups A8 and A10 and in the n. raphé dorsalis after (3H)-dopamine- and (3H)-serotonin-injection, however in the cortex and in the thalamus after (3H)-D-aspartate-injection into the rat caudoputamen and in the n. raphé dorsalis after (3H)-serotonin-injection but in the caudoputamen after (3H)-GABA-injection into the substantia nigra - all these patterns indicate a retrograde labeling with a certain - partly transmitter specific - selectivity in the pathways concerned. Transmitter related, retrograde transport may become a useful neuro-anatomical method. The cell biology and a possible biological function of the phenomenon remain to be investigated.
The retrograde axoplasmic transport of iodinated nerve growth factor (125I-NGF) was markedly altered by systemic acrylamide treatment. Single doses of acrylamide (25 to 100 mg/kg, ip) inhibited the retrograde transport of 125I-NGF in a dose-dependent manner within 12 hr after administration. A dose of acrylamide (15 mg/kg, ip) which did not alter retrograde transport when given as a single dose, markedly inhibited retrograde transport when given repeatedly. Alterations in retrograde transport appeared prior to detectable alterations in peripheral nerve function and correlated with cumulative dose of acrylamide. These data suggest that single doses of acrylamide produce a biochemical lesion which accumulates to produce neuropathy. Altered retrograde axoplasmic transport may reflect the primary biochemical event responsible for the induction of neuropathy by acrylamide.
A single intraperitoneal injection of beta, beta'-iminodipropionitrile (IDPN) at a dose of 1.5 g/kg was given to 4-week-old rats. Immediately following, or at 1, 2, 3, 5, 10, and 15 weeks after IDPN injection, [35S]methionine was introduced into the anterior horn area of the lumbar cord. Labeled axonal proteins in the sciatic nerve were analyzed electrophoretically and fluorographically at 5, 10, and 15 weeks post-labeling. Labeled neurofilament proteins halt for a short period just after IDPN injection, then continue migrating distally, though at a slower rate, and finally the transport of affected neurofilament proteins completely recovers by 6 weeks post-labeling.
Cerebral cortical projections from the forelimb motor cortex, as defined by intracortical microstimulation where movements were evoked at low current intensities (less than 15 microA), were examined in normal rats and in adult rats that sustained neonatal hemicerebellectomy. The distribution pattern of cortical efferent projections in normal rats generally appeared more restricted than previously described. This restricted distribution is attributed to the use of WGA/HRP as the axonal tracing method and to the electrophysiological definition of the injection site as the motor cortex. The observed remodeling of the corticobulbar projections, seen after cerebellar lesions in the young, largely confirmed previous reports. Moreover, no alterations in the laterality of distribution in corticospinal projection were found. Aberrant corticospinal projections were sought in an effort to provide an anatomical basis to a previous description of abnormally low-threshold ipsilateral forelimb responses evoked from the motor cortex in adult rats after neonatal cerebellar lesions. This apparent absence of corticospinal tract remodeling after neonatal hemicerebellectomy suggests that the abnormal responses are mediated by the normal corticospinal pathways. This possibility is discussed in terms of an alteration in the spinal circuits that may change the responsiveness of spinal motoneurons to a given pyramidal discharge.
The design and construction of a multiple proportional counter, a position-sensitive detector of ionizing radiation, are described. Both the mechanical and electronic aspects are discussed. Testing procedures are outlined, and test values are cited.
The rapid bidirectional transport of dopamine beta-hydroxylase (DBH) in adrenergic axons provides a means of analyzing the life cycle of adrenergic storage vesicles. We compared the physical characteristics of DBH-containing particles traveling to or returning from the terminal varicosities of ligated rat sciatic nerves. Density gradient centrifugation and Sephacryl S1000 gel-permeation chromatography were used to fractionate extracts from nerve segments proximal or distal to the ligatures. A series of experiments indicated the existence of at least two populations of rapidly transported DBH-containing particles, a "light" 85-nm particle and a larger "dense" 120-nm particle. The 85-nm particles were prevalent in unligated nerve, but accounted for only one-third of the total anterogradely transported DBH activity accumulated after 18 h. The 120-nm particles were barely detectable in the unligated nerve, but they accumulated at twice the rate of the 85-nm particles and accounted for the rest of the anterogradely transported particulate DBH activity. These two populations of particles were readily isolated from proximal nerve extracts by sucrose density gradient centrifugation. Similar-appearing dense and light peaks of particulate DBH activity were obtained from distal nerve extracts. Much of the retrogradely transported DBH of the extracts, however, was associated with large particles (greater than 300 nm) not resolved by Sephacryl S1000. Retrogradely transported exogenous NGF was found only in the dense sucrose gradient peak. We propose that the 85-nm DBH-containing particles correspond to "large dense-cored vesicles," and that the 120-nm particles are derived from the dense tubules visualized in adrenergic nerves by the chromaffin reaction.
The ability of the cholecystokinin (CCK) receptor antagonists, MK-329 and L-365,260, to selectively inhibit 125I-Bolton-Hunter-CCK8 binding to ligated rat vagus nerve in vitro was examined at concentrations ranging from 10(-10) M to 10(-6) M. Both antagonists inhibited binding to CCK binding sites accumulating proximal to ligatures on the cervical vagus. Incubation of nerve sections in the presence of both antagonists produced an additive effect, indicating that both CCK-A and CCK-B binding sites are transported towards the periphery. In contrast, CCK binding sites accumulating distal to the ligature possessed the pharmacological characteristics of the CCK-B receptor sub-type only.
Visual cortex, including areas 17, 18, and sometimes 19, was injected with tritiated leucine. Terminal labelling could be detected by autoradiography in the dorsocaudal part of the ipsilateral claustrum in all cases.
Na+,K+-ATPase levels were measured in different segments of rat sciatic nerves by in vitro binding of [3H]ouabain. Binding sites were found to accumulate on both sides of a ligature tied on the sciatic nerve, indicating an anterograde and retrograde axoplasmic transport of Na+,K+-ATPase. Accumulation of Na+,K+-ATPase at the ligature was time dependent and appeared to occur through fast axoplasmic transport mechanisms. This accumulation on both sides of the ligature was also visualized by autoradiographic studies in longitudinal section of sciatic nerves using [3H]ouabain.