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PubMed1990

Axonal transport of synaptic vesicles and muscarinic receptors: effect of protein synthesis inhibitors.

The effect of cycloheximide, a protein synthesis inhibitor, was studied on the axonal transport of noradrenergic synaptic vesicles and presynaptic muscarinic receptors, identified by in vitro binding of [3H]dihydrotetrabenazine and [3H]quinuclidinylbenzilate, respectively, in rat sciatic nerve. Cycloheximide (1.5 mg/kg) administered subcutaneously 2 h before ligation decreased by approximately 50% the accumulation of vesicles and receptors in the proximal segment above the ligature placed on the nerve; its action was detectable after a lag period of 10 h and disappeared 96 h after administration. Double ligatures were placed on the nerve at various time intervals between the first (distal) and the second (proximal) ligature, and the accumulation of vesicles and receptors proximal to the second ligature was measured; the first ligature diminished the accumulation above the second ligature. At an interval of 96 h between the first and the second ligature, cycloheximide completely prevented the accumulation of vesicles and receptors proximal to the second ligature. The effects of double ligatures and the response to cycloheximide treatment can best be explained on the assumption that an important proportion of synaptic vesicles and presynaptic receptors is being recycled in the nerve cell bodies after retrograde transport.

Animals↗
PubMed2006

Ferroportin in the postnatal rat brain: implications for axonal transport and neuronal export of iron.

This study mapped the distribution of ferroportin in the developing rat brain using Wistar rats aged postnatal (P) days P7, P21, and P70 (adult). Ferroportin immunoreactivity was observed in neurons throughout the CNS regardless of the age of the animals studied. The neuronal labeling was detected in both perikarya, and axons and dendrites. The labeling intensity within the neurons varied among the different ages of the rats with an overall higher ferroportin immunoreactivity seen at P21, particularly in axons and white matter tracts. The neuronal labeling was high in the neocortex, striatum, hippocampus, brain stem nuclei, deep cerebellar nuclei, catecholaminergic neurons, and reticular nuclei, and particularly high in neurons of the mesencephalic trigeminal nucleus and medial habenular nucleus. In axonal tracts, ferroportin immunoreactivity was high in fibers of the internal capsule, fimbria, mamillothalamic tract and the habenulo-interpedunculo pathway. Slight ferroportin immunoreactivity was observed in oligodendrocytes and differentiating macrophages that invade the postnatal brain. The finding of a pronounced content of ferroportin in axons of the developing brain are in keeping with the idea of elevated axonal transport and export of iron possibly because of higher metabolic needs.

Animals↗
PubMed1983

Quantitative demonstration of the retrograde axonal transport of endogenous nerve growth factor.

The level of endogenous nerve growth factor (NGF) in rat sciatic nerve was determined using a highly sensitive two-site enzyme immunoassay. After crushing this nerve NGF accumulated linearly distal to the crush during the first 12 h to reach levels 13-fold higher than in the uncrushed contralateral side. In contrast, proximal to the crush NGF levels approached or were below the detection limit of the assay. The asymmetrical distribution of NGF on the two sides of a crush is direct evidence for the retrograde axonal transport of endogenous NGF.

Animals↗
PubMed1982

The differential distribution and relationship of serotoninergic and peptidergic fibers to sympathoadrenal neurons in the intermediolateral cell column of the rat: a combined retrograde axonal transport and immunofluorescence study.

The preganglionic sympathetic neurons in the intermediolateral cell column of the thoracic and upper lumbar segments of the spinal cord which innervate the chromaffin cells in the adrenal medulla, sympathoadrenal preganglionic neurons, were identified by the method of retrograde axonal transport of the fluorescent dyes Fast Blue and True Blue. In rats, Fast Blue or True Blue was injected into the medulla of the left adrenal gland. After a survival period of 5 days, the animals were perfusion fixed, the thoracic and lumbar spinal cord sectioned and processed for the immunofluorescent localization of met-enkephalin, neurophysin, oxytocin, serotonin, somatostatin and substance P immunoreactivity. Neuronal perikarya which were retrogradedly-labeled with Fast Blue or True Blue were observed in the intermediolateral cell column from the T1 to the L2 spinal cord segments. The distribution of the sympathoadrenal neurons was determined by counting the number of retrogradedly-labeled neurons per spinal cord segment. In the five animals used for quantifying the sympathoadrenal preganglionic neurons, the majority (72.3%) of the retrogradely-labeled neurons counted per spinal cord were located within the T7-T12 segments. The T9 segment contained the largest average number (20.1%) of retrogradely-labeled cells in a single segment. Met-enkephalin, serotonin and substance P immunoreactive fibers were prominent in the intermediolateral cell column, whereas oxytocin, neurophysin and somatostatin immunoreactive fibers were sparse. The met-enkephalin, serotonin and substance P fibers were seen surrounding both unlabeled and retrogradely-labeled neurons; somatostatin fibers appeared to preferentially contact retrogradely-labeled neurons; whereas, the neurophysin and oxytocin fibers were not found in proximity to retrogradely-labeled neurons. Met-enkephalin, neurophysin, oxytocin, somatostatin and substance P immunoreactivity were depleted in the intermediolateral cell column below the level of a spinal cord transection. Serotonin immunoreactivity was depleted in the intermediolateral cell column below the level of the transection for five to six segments, but sparse networks of immunoreactive fibers were observed in both the intermediolateral cell column and the ventral horn in more caudal segments. Met-enkephalin, serotonin, somatostatin and substance P immunoreactivity were decreased in both the contralateral and ipsilateral intermediolateral cell column below the level of a spinal cord hemisection, suggesting that both crossed and uncrossed descending pathways exist. Neurophysin and oxytocin immunoreactivity were depleted below the level of the hemisection in the ipsilateral intermediolateral cell column without noticeable decrease in the level of immunoreactivity in the contralateral intermediolateral cell column, suggesting that a decussation does not occur at the level of the spinal cord, but may exist above the level of the hemisection...

Adrenal Medulla↗
PubMed1994

Retrograde axonal transport of LIF is increased by peripheral nerve injury: correlation with increased LIF expression in distal nerve.

Leukemia inhibitory factor (LIF) is a cytokine that affects the survival and differentiation of certain neuronal populations in vitro. To identify LIF-responsive neurons in the adult rat, we have demonstrated retrograde axonal transport of 125I-LIF to sensory and motor neurons. The accumulation of 125I-LIF by both cell types was significantly increased by prior sciatic nerve crush. Retrograde transport of 125I-LIF was inhibited by excess unlabeled LIF but not by related cytokines, indicating a specific receptor-mediated mechanism. Northern blot analysis revealed LIF expression in peripheral nerve that was increased in distal segments after axotomy. The correlation between LIF expression and increased retrograde transport following injury suggests that LIF plays a role in peripheral nerve regeneration.

Animals↗
PubMed2006

JNK mediates pathogenic effects of polyglutamine-expanded androgen receptor on fast axonal transport.

Expansion of the polyglutamine (polyQ) stretch in the androgen receptor (AR) protein leads to spinal and bulbar muscular atrophy (SBMA), a neurodegenerative disease characterized by lower motor neuron degeneration. The pathogenic mechanisms underlying SBMA remain unknown, but recent experiments show that inhibition of fast axonal transport (FAT) by polyQ-expanded proteins, including polyQ-AR, represents a new cytoplasmic pathogenic lesion. Using pharmacological, biochemical and cell biological experiments, we found a new pathogenic pathway that is affected in SBMA and results in compromised FAT. PolyQ-AR inhibits FAT in a human cell line and in squid axoplasm through a pathway that involves activation of cJun N-terminal kinase (JNK) activity. Active JNK phosphorylated kinesin-1 heavy chains and inhibited kinesin-1 microtubule-binding activity. JNK inhibitors prevented polyQ-AR-mediated inhibition of FAT and reversed suppression of neurite formation by polyQ-AR. We propose that JNK represents a promising target for therapeutic interventions in SBMA.

Analysis of Variance↗
PubMed1995

Retrograde axonal transport of glial cell line-derived neurotrophic factor in the adult nigrostriatal system suggests a trophic role in the adult.

The recently cloned, distant member of the transforming growth factor beta (TGF-beta) family, glial cell line-derived neurotrophic factor (GDNF), has potent trophic actions on fetal mesencephalic dopamine neurons. GDNF also has protective and restorative activity on adult mesencephalic dopaminergic neurons and potently protects motoneurons from axotomy-induced cell death. However, evidence for a role for endogenous GDNF as a target-derived trophic factor in adult midbrain dopaminergic circuits requires documentation of specific transport from the sites of synthesis in the target areas to the nerve cell bodies themselves. Here, we demonstrate that GDNF is retrogradely transported by mesencephalic dopamine neurons of the nigrostriatal pathway. The pattern of retrograde transport following intrastriatal injections indicates that there may be subpopulations of neurons that are GDNF responsive. Retrograde axonal transport of biologically active 125I-labeled GDNF was inhibited by an excess of unlabeled GDNF but not by an excess of cytochrome c. Specificity was further documented by demonstrating that another TGF-beta family member, TGF-beta 1, did not appear to affect retrograde transport. Retrograde transport was also demonstrated by immunohistochemistry by using intrastriatal injections of unlabeled GDNF. GDNF immunoreactivity was found specifically in dopamine nerve cell bodies of the substantia nigra pars compacta distributed in granules in the soma and proximal dendrites. Our data implicate a specific receptor-mediated uptake mechanism operating in the adult. Taken together, the present findings suggest that GDNF acts endogenously as a target-derived physiological survival/maintenance factor for dopaminergic neurons.

Animals↗
PubMed1989

Fluorometric comparisons of the retrograde axonal transport of true blue and diamidino yellow from the rat caudate-putamen.

The retrograde tracers true blue and diamidino yellow were injected into the caudate-putamen of adult rats which were allowed to survive for periods of 12 to 480 h after these injections. The retrograde axonal transport of these tracers was assessed by microphotometric measurement of the intensity of fluorescence in labelled neurones in the following three different sources of afferents to the caudate-putamen: the substantia nigra pars compacta; the parafascicular nucleus; and the dorsal raphe nucleus. It took respectively 12, 24 and 48 h for neurones in the substantia nigra, parafascicular nucleus and dorsal raphe nucleus to become retrogradely labelled. The average fluorescent intensity was greatest after 96-168 h but this highest value, and the subsequent decline, in fluorescence varied considerably between different tracers and different pathways. Neither axonal length nor neuronal activity correlate well with dynamics of build up and decline in fluorescence, but axonal collateralisation and diffuseness of terminals are associated with slower accumulation and more rapid removal of the tracers. Some neurones labelled with true blue retain their fluorescence better than those labelled with diamidino yellow but these differences are overshadowed by differences between different pathways in this respect.

Amidines↗
PubMed1978

Uptake and retrograde axonal transport of various exogenous macromolecules in normal and crushed hypoglossal nerves.

Macromolecular tracers were injected into the tongue or around a crush in mouse hypoglossal nerves. At various times thereafter, the tracers were histochemically localized on the basis of peroxidase activity. The distribution of reaction product was then examined using light microscopy in order to study the influence of molecular charge and size on uptake and retrograde axonal transport from the periphery or from the crushed axon. Of various proteins with peroxidase activity, horseradish peroxidase and cytochrome-c showed the greatest penetration into axons proximal to the crush. Following injection into the tongue, intra-axonal cytochrome-c was detectable in some of the peripheral branches but not any of the other proteins. Retrograde transport to the nerve cell bodies was demonstrated for horseradish peroxidase and cytochrome-c, both from the tongue and from the axonal crush but not for microperoxidase, myoglobin, hemoglobin, lactoperoxidase and catalase. The number of neuronal cell bodies having detectable reaction product was higher for peroxidase-injected than for cytochrome-c-injected animals. Ferritin and iron-dextran (Imferon) also accumulated in hypoglossal neurons, but this could be detected only after repeated injections into the tongue. Uptake and retrograde transport from the tongue or from the crush occurred both for anionic and for cationic horseradish peroxidase. This is interpreted as evidence against absolute specificity in the uptake and transport of macromolecules on the basis of electrical charge.

Animals↗
PubMed1987

[Age-related characteristics of the effect of denervation and axonal transport blockade on the electrical characteristics of skeletal muscle fibers].

The denervation and colchicine-induced changes of resting MP, electroexcitability threshold, amplitude and duration of the AP peak were studied in m. extensor digitorum longus and m. soleus of adult and old rats. In the latter, the neurotrophic control of the sarcolemma electrical properties was weakened, this being more obvious in the red muscle. The age changes of neurotrophic control are one of the causes of disturbances of the sarcolemma electrical properties in skeletal muscle fibers of old animals. The weakening of neurotrophic control may be due to the decrease of axonal transport rate in old age.

Aging↗
PubMed1989

Dynein is the motor for retrograde axonal transport of organelles.

Vesicular organelles in axons of nerve cells are transported along microtubules either toward their plus ends (fast anterograde transport) or toward their minus ends (retrograde transport). Two microtubule-based motors were previously identified by examining plastic beads induced to move along microtubules by cytosol fractions from the squid giant axon: (i) an anterograde motor, kinesin, and (ii) a retrograde motor, which is characterized here. The retrograde motor, a cytosolic protein previously termed HMW1, was purified from optic lobes and extruded axoplasm by nucleotide-dependent microtubule affinity and release; microtubule gliding was used as the assay of motor activity. The following properties of the retrograde motor suggest that it is cytoplasmic dynein: (i) sedimentation at 20-22 S with a heavy chain of Mr greater than 200,000 that coelectrophoreses with the alpha and beta subunits of axonemal dynein, (ii) cleavage by UV irradiation in the presence of ATP and vanadate, and (iii) a molecular structure resembling two-headed dynein from axonemes. Furthermore, bead movement toward the minus end of microtubules was blocked when axoplasmic supernatants were treated with UV/vanadate. Treatment of axoplasmic supernatant with UV/vanadate also blocks the retrograde movement of purified organelles in vitro without changing the number of anterograde moving organelles, indicating that dynein interacts specifically with a subgroup of organelles programmed to move toward the cell body. However, purified optic lobe dynein, like purified kinesin, does not by itself promote the movement of purified organelles along microtubules, suggesting that additional axoplasmic factors are necessary for retrograde as well as anterograde transport.

Adenosine Triphosphatases↗
PubMed1976

Dynamics of fast axonal transport.

A phenomenological model of the process of fast axoplasmic transport is presented. The process was conceived of as occurring in two parts: (a) synthesis and storage of material in a cytoplasmic pool; (b) release from the pool and transport distally along the axon. Considering the fate of labeled proteins, the activity at points along the axon relfects events occurring earlier within the pool through the relationship: g(x,t) = const f(t - x/v); where g(x,t) represents axonal activity, f(t) the pool's activity, and v is the transport speed. Using the idea that when there is no further input of radioactivity into the pool its activity declines exponentially due to export of material to the axon. I generalized this concept to the case where activity enters and leaves the pool simultaneously. The model contains two parameters: the relative turnover rate of the pool, alpha, and T, an interval characteristic of the time of synthesis. From this model, the experimental data is unfolded and yields values for these parameters of alpha = 0.004 min-1 and T approximately 60 min.

Axonal Transport↗
PubMed1997

Location of efferent terminals of the primate flocculus and ventral paraflocculus revealed by anterograde axonal transport methods.

Efferents of the flocculus (FL) and ventral paraflocculus (VP) were examined in seven anesthetized Macaca fuscata by anterograde axonal transport method using wheat germ agglutinin-conjugated horseradish peroxidase or phaseolus vulgaris leucoagglutinin. Several major foci of axon terminals were found in the vestibular nuclear complex and cerebellar nuclei. A difference was seen in the location of efferent terminals between the FL and VP. When the tracer covered the FL, labeled axon terminals were located within the medial and ventrolateral parts of the medial vestibular nucleus, superior vestibular nucleus and y-group. When the tracer covered the VP, labeled axon terminals were located within the caudo-ventral part of posterior interpositus and dentate nuclei, in addition to the medial and ventrolateral parts of the medial vestibular nucleus, superior vestibular nucleus and y-group. Labeled terminals were virtually absent in the basal interstitial nucleus of the cerebellum. On the points of neo- or paleo-cerebellar cortex fiber connections, these results correspond to our previous anatomical observations that the FL received mossy fiber afferents mainly from the vestibular system and nucleus reticularis tegmenti pontis and very little from the pontine nuclei, whereas the VP received mossy afferents mainly from the nucleus reticularis tegmenti pontis and pontine nuclei and very little from the vestibular system. These anatomical observations are consistent with a hypothesis in our previous anatomical and physiological study that the primate FL and VP mediate rather different functional roles in the oculomotor control.

Animals↗
PubMed1983

Retrograde axonal transport of intravenously administered 125I-nerve growth factor in rats with streptozotocin-induced diabetes.

We have previously demonstrated a reproducible axonopathy, involving but not confined to sympathetic neurons, which involves selectively the mesenteric nerves of chronically diabetic rats. We describe a series of experiments aimed at correlating changes in the retrograde transport of 125I-nerve growth factor (125I-NGF) with development of the lesions. 125I-NGF was injected systemically and the time course of accumulation compared in superior cervical ganglion (SCG) and superior mesenteric ganglion (SMG). 125I-NGF accumulated in the SCG with a sharp peak at 12 h, whereas in the SMG, accumulation reached a plateau, remaining at relatively constant amounts for 8 h before decreasing. There was a marked decrease in the accumulation of 125I-NGF (averaging 44% in 11 separate experiments) in the SMG at early times (approximately 12 h). These decreases were seen in animals diabetic for times ranging from 2 days to 10 mo. In contrast, no consistent decrease was observed in the SCG. The time course of 125I-NGF accumulation was unaltered in the SCG of diabetic rats but was clearly retarded in the SMG of diabetic animals. Morphometric examination of the SMG of diabetic animals and controls showed little or no atrophy or neuron loss due to diabetes. We conclude that decreases in the retrograde transport of NGF occur selectively in those ganglia (SMG) serving the alimentary tract in which mesenteric nerves develop distal axonopathy, but not in ganglia whose nerves do not ultimately develop such lesions (SCG). The decreases in retrograde transport precede the development of morphologic lesions in this system. These results are consistent with the suggestion that impairment of axonal transport may play a role in the development of axonopathy.

Animals↗
PubMed1987

Enhanced axonal transport of receptor-bound opiate in ethanol-treated rats.

The retrograde transport of receptor-bound opiate was markedly enhanced in the vagus nerves of rats housed for 25 days in an atmosphere of ethanol vapor. This increase disappeared after 8 days of withdrawal as did the animal preference for ethanol. In contrast, the axonal transport of muscarinic receptors in sciatic nerves was slightly reduced. This provides more evidence for the idea that chronic alcoholization and morphine addiction share a common denominator and that the retrograde transport of receptor-bound signal molecules represents a link between the synapses and the cell-body of neurones.

Animals↗