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PubMed1994

The role of conditioning factors in the formation of growth cones and neurites from the axon stump after axotomy.

Knowledge of the cellular events that underlie initiation of outgrowth is crucial to understanding regulation of development and regeneration of the nervous system. This study utilized a culture preparation in which growth cone formation could be studied independent of cellular responses to the presence of conditioning factors. Identified neurons were removed from the buccal ganglion of the mollusc, Helisoma trivolvis, and plated into defined culture medium. A large growth cone formed at the end of the attached axon stump. Although this axonal growth cone exhibited filopodial and lamellipodial activity, it did not advance across the substrate, suggesting that growth cone formation and motility were independent of the presence of conditioning factors. Axonal growth cones of identified neurons B19 and B5 exhibited differences in their morphological and behavioral properties. In response to the addition of conditioning factors, several new neurites extended from the periphery of the axonal growth cone. Extension of outgrowth from the axonal growth cone was accompanied by a redistribution of cytoskeletal elements in the axonal growth cone. Cytoskeletal staining revealed a loss of the peripheral actin filament network and microtubules were found to extend into the peripheral lamellipodium of the axonal growth cone, an area normally devoid of microtubule staining. Thus, these experiments indicate that growth cone formation is an intrinsic property of the distal axon stump and that neurite extension from this structure involves reorganization of the neuronal cytoskeleton.

Animals↗
PubMed1994

Effect of axotomy on nitric oxide-dependent cyclic GMP production of rat superior cervical sympathetic ganglia in response to norepinephrine.

Cyclic GMP (cGMP) production in superior cervical sympathetic ganglia (SCG) isolated from rats was markedly enhanced (approx. 4.5-fold) by the addition of L-arginine (L-Arg, 100 microM) plus an inhibitor (3-isobutyl-1-methylxanthine) for cGMP hydrolytic enzyme during in vitro aerobic incubation at 37 degrees C for 10 min. This accelerated accumulation of ganglionic cGMP was effectively reversed by approximately 50% when NG-monomethyl-L-arginine (L-NMMA, 50 microM), a compound that inhibits nitric oxide (NO) synthesis from L-Arg, was further added to the medium. These observations imply that cGMP production with possible involvement of a mechanism depending on NO synthesis may be functionally operating in the ganglionic tissue. Application of norepinephrine (NE, 50 microM) with pargyline, a monoamine oxidase inhibitor, to the medium also elevated the ganglionic cGMP level at a magnitude comparable to that shown by L-Arg addition, while co-addition of L-NMMA largely (approx. -60%) eliminated the NE-induced increase in ganglionic cGMP formation. In axotomized SCG one week prior to examination, where sympathetic neurons were degenerated and reactive proliferation of glial cells was in progress, augmented stimulatory effect (more than 8-fold) of NE on cGMP production was seen compared to that caused in unoperated ganglia or in SCG 1 week following denervation, where preganglionic cholinergic nerve terminals were destroyed. When axotomized SCG were transferred to in vitro incubation conditions, addition of an alpha-1 adrenergic antagonist, prazosin (1 microM) to the medium virtually reduced the accelerative effect of NE to less than 25% of the NE-induced cGMP level in the tissue.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1992

Preprogalanin mRNA is increased in vagal motor neurons following axotomy.

Expression of preprogalanin and tyrosine hydroxylase mRNA was examined in the rat dorsal vagal complex following nodose ganglionectomy and cervical vagotomy, using in situ hybridization of specific 35S-labelled oligonucleotides. Seven days after unilateral cervical vagotomy (and nodose ganglionectomy), neurons in the ipsilateral dorsal motor nucleus of the vagus and nucleus ambiguus expressed 6- to 10-fold increased levels of preprogalanin mRNA. In contrast, tyrosine hydroxylase mRNA was no longer expressed by cells of the dorsal motor nucleus of the vagus after the lesion. These results demonstrate that changes in the expression of the galanin and tyrosine hydroxylase genes occur in vagal motor neurons following lesion of their axons. More generally, these results, and those from other laboratories, demonstrate that specific alterations of neuropeptide and neurotransmitter production, are part of the reactive process activated by nerve injury.

Animals↗
PubMed1992

Long-term serotonin reinnervation of the suprachiasmatic nucleus after 5,7-dihydroxytryptamine axotomy in the adult rat.

We present here immunohistochemical evidence that serotonin (5-HT) reinnervation in the suprachiasmatic nucleus (SCN) of adult rats, after intraventricular administration of 5,7-dihydroxytryptamine, is more extensive than formerly believed. The first fibers appeared at 4 months and developed until more than 7 months. However, comparison with age-matched controls showed that, even 24 months post-lesion, the density of 5-HT innervation remained abnormally low. At the electron microscopic level, many synaptic contacts were found to have been re-established. The cellular mechanisms possibly responsible for incomplete 5-HT reinnervation in the SCN are discussed.

5,7-Dihydroxytryptamine↗
PubMed1983

The corticopontine projection: axotomy-induced loss of high affinity L-glutamate and D-aspartate uptake, but not of gamma-aminobutyrate uptake, glutamate decarboxylase or choline acetyltransferase, in the pontine nuclei.

The corticopontine fibres were severed in the crus cerebri in rats and mice by a stereotaxically operated retractable wire-knife. The pontine nuclei were microscopically dissected from fresh slices of rats and synaptosome-containing homogenates were prepared. The high affinity uptake of radiolabelled L-glutamate (L-Glu) and D-aspartate (D-Asp) was heavily reduced five days after the lesions. The uptake was further reduced after bilateral (-75% for D-Asp and -65% for L-Glu) than after unilateral lesions (-55% for D-Asp and -45 to 50% for L-Glu on the lesioned side.) The molar ratio of the uptakes of D-Asp and L-Glu was consistently lower in pons after transection of the cortical afferents than normally (-28% after bilateral lesions). gamma-Aminobutyrate uptake and glutamic acid decarboxylase were not changed. Choline acetyltransferase was increased (+53%) after unilateral lesions, but not altered after bilateral lesions. Autoradiograms of slices from mice, incubated with tritium-labelled amino acids and fixed in glutaraldehyde, showed high affinity uptake sites for D-Asp to be enriched in the pontine nuclei, compared to neighbouring structures. After partial lesion of the crus cerebri the uptake was reduced in the area with degenerated corticopontine afferents. gamma-Aminobutyrate uptake sites were relatively less concentrated in the pontine nuclei than D-Asp uptake sites. The results indicate, along with the previous demonstration of Ca-dependent K-induced release of D-[3H]aspartate from the corticopontine terminals, that glutamate and/or aspartate may be transmitters in this pathway. The results also suggest that acidic amino acid uptake sites may differ in their relative transport rates for aspartate and glutamate.

Animals↗
PubMed1983

Degenerative and regenerative changes in central projections of glossopharyngeal and vagal sensory neurons after peripheral axotomy in cats: a structural basis for central reorganization of arterial chemoreflex pathways.

Hypoxic hyperventilation in cats is a reflex normally initiated by afferent impulses originating in the carotid body and conducted to the brain stem by the carotid sinus nerves. The reflex response is abolished acutely after section of carotid sinus nerves and excision of the carotid bodies; but, chronically, there is a chemoreflex restoration which is mediated by the aortic body via the aortic depressor nerves. The restoration is associated temporally with changes in efficacy of ventilatory reflexes elicited by electrically stimulating carotid sinus and aortic depressor nerves, and these changes are postulated to reflect a central reorganization of the reflex pathways. In the present study, histological and ultrastructural techniques were used to investigate the neuroanatomical basis of the reorganization. The brain stem of the cat was examined using the Fink-Heimer silver stain to determine if degenerating axons were present following section of the carotid sinus nerve peripheral to its sensory ganglion. Degeneration was found 4-15 days postoperatively and the distribution of the axons corresponded with that reported for central projections of carotid sinus nerves labeled by transganglionic transport of horseradish peroxidase. The fine structure of nerve terminals in nucleus tractus solitarius was then examined with electron microscopy after cutting the vagus and glossopharyngeal nerves unilaterally peripheral to the sensory ganglia. Structural changes consistent with nerve terminal degeneration were observed 4-91 days postoperatively, and presumptive axonal sprouts were seen at 56-91 days.(ABSTRACT TRUNCATED AT 250 WORDS)

Afferent Pathways↗
PubMed1984

Axotomy increases glycogen phosphorylase activity in motoneurones.

The relative distribution of glycogen phosphorylase a and b in the lumbar spinal cord of the adult rat following either transection or crush of the sciatic nerve has been studied. The activity of the glycogen phosphorylase was measured histochemically by its capacity to convert glucose-1-phosphate to glycogen which was then stained with iodine. Prior to any treatment, the enzyme was largely in its inactive b form. Sciatic section and crush produced a transient (24 h) decrease in the amount of the active glycogen phosphorylase a in the sciatic motoneurone pool. Fourteen days post-transection, but not crush, a marked increase in the level of the active glycogen phosphorylase a form of the enzyme could be detected in the axotomised motoneurones which persisted for up to 6 weeks. No equivalent changes occurred in the axotomized dorsal root ganglion cells. Glycogen phosphorylase although normally present in neurones in its inactive b form can be converted to the active a form by calcium or adenosine 3':5'-phosphate. The substantial increase in the level of glycogen phosphorylase a in axotomized motoneurones may be a reflection of an increased calcium influx into these cells due to the development of abnormally hyperexcitable membranes and the appearance of dendritic spikes that is known to occur in these motoneurones.

Adenosine Monophosphate↗
PubMed1992

Calcitonin gene-related peptide in rat spinal cord motoneurons: subcellular distribution and changes induced by axotomy.

Using light and electron microscopy, a study has been made of the changes of calcitonin gene-related peptide-like immunoreactivity in rat lumbar spinal cord motoneurons during cell body response to sciatic nerve injury. At light microscopy level, calcitonin gene-related peptide-like immunoreactivity was evaluated using an indirect immunofluorescence technique combined with Fast Blue retrograde tracing and a peroxidase-antiperoxidase procedure. The calcitonin gene-related peptide changes to sciatic nerve transection and crushing were compared. Calcitonin gene-related peptide-like immunoreactivity was transiently increased after the peripheral nerve lesion, but the response was sustained for a longer period when the peripheral nerve was transected and nerve regeneration prevented. The first changes in calcitonin gene-related peptide-like immunoreactivity were detected four days after nerve crush or transection. In animal spinal cords to which nerve crush had been applied, the maximal enhancement of immunoreactivity was found 11 days after lesion. This was followed by a gradual decline, normal levels being attained 45 days after nerve crushing. When the nerve was transected, the response was similar, but the maximal calcitonin gene-related peptide-like immunoreactivity was maintained over a period of between 11 and 30 days. As with crushing, an important decrease was observed after 45 days. The ultrastructural compartmentation of calcitonin gene-related peptide-like immunoreactivity was studied using either peroxidase-antiperoxidase method or immunogold labelling. Calcitonin gene-related peptide-like immuno-reactivity was located in restricted sacs of the Golgi complex, multivesicular bodies, small vesicles and tubulo-vesicular structures. Large, strongly labelled vesicles resembling secretory granules were also observed in neuronal bodies. Our results reveal that the increase of calcitonin gene-related peptide in motoneurons is a relevant change the cell body undergoes in response to peripheral injury. The ultrastructural location of the peptide distribution suggests specific compartmentation on tubulo-vesicular structures connected with the Golgi complex which form a network in the neuronal cytoplasm. The distribution pattern observed may be related to the sorting and delivery of calcitonin gene-related peptide to secretory vesicles.

Animals↗
PubMed1994

Differential regulation of phospholipase C isozymes in the rat facial nucleus following axotomy.

The expression of phospholipase C isozymes and phosphatidylinositol 4-kinase in the rat facial nucleus was studied using in situ hybridization at various times after unilateral crushing and resectioning the facial nerve. The level of phospholipase C alpha messenger RNA increased from three days to one week after the operation. On the other hand, an apparent reduction in the level of phospholipase C beta 1 occurred from three days to one week after resection. After either crushing or resection, phospholipase C gamma 1 messenger RNA levels were not noticeably changed. As phosphatidylinositol 4-kinase is the rate-limiting enzyme for the production of phosphatidylinositol 4,5-bisphosphate, which is the preferred substrate for phospholipase C, we investigated the expression of phosphatidylinositol 4-kinase messenger RNA. The level of phosphatidylinositol 4-kinase messenger RNA was decreased one day after axonal injury. Among phospholipase C isozymes, phospholipase C alpha is up-regulated. As the structure of phospholipase C alpha is different from other isozymes, phospholipase C alpha is supposed to have a different function. The present unique up-regulation of phospholipase C alpha may suggest a novel function in nerve regeneration. Phospholipase C beta 1 is down-regulated, as is phosphatidylinositol 4-kinase. This suggests that the signal transmission system using a G-linked receptor is broken down after nerve injury. On the other hand, phospholipase C gamma 1, which is related to the receptor tyrosine kinase, does not demonstrate any transcriptional regulation after nerve injury.

1-Phosphatidylinositol 4-Kinase↗
PubMed1995

Galanin expression in sympathetic ganglia after partial axotomy is highly localized to those neurons that are axotomized.

The neuropeptide phenotype of adult sympathetic neurons changes dramatically after postganglionic nerve transection. Studies, thus far, have been done on the superior cervical ganglion; however, one limitation of this preparation is that it is necessary to transect the postganglionic axons quite close to the ganglion. In the present study, we examined the effects of axonal damage on galanin-like immunoreactivity in the middle and inferior cervical ganglion complex. With these ganglia, it is possible to transect postganglionic axons at a considerable distance from their cell bodies and, therefore, to examine the extent to which local tissue damage, rather than specific axonal transection, is required for these changes in neuropeptide phenotype to occur. The anatomy of this system also allowed us to determine the extent to which the changes in galanin expression are restricted to those neurons that have been axotomized. The axons of a small population of the neurons in the middle and inferior cervical ganglia complex project into the cervical sympathetic trunk. Within two days after this trunk was transected, there was an increase in the level of galanin-like immunoreactivity in the complex and in the number of immunostained principal neurons. These neurons were concentrated primarily in the most rostral part of the complex. An increase in galanin-like immunoreactivity also occurred in response to the systemic administration of the sympathetic neurotoxin 6-hydroxydopamine. In that case, many more neurons were affected than after transection of the cervical sympathetic trunk, and the neurons were distributed evenly throughout the ganglion complex.(ABSTRACT TRUNCATED AT 250 WORDS)

Amidines↗
PubMed1995

Quantitative autoradiographic localization of [125I-Tyr8]bradykinin receptor binding sites in the rat spinal cord: effects of neonatal capsaicin, noradrenergic deafferentation, dorsal rhizotomy and peripheral axotomy.

In vitro receptor autoradiography was used to localize, quantify and characterize [125I-Tyr8]bradykinin binding sites in all major spinal cord segments of normal rats and animals subjected to various chemical treatments and surgical lesions. [125I-Tyr8]bradykinin specific binding sites were predominantly located to superficial laminae of the rat dorsal horn, with the substantia gelatinosa showing the highest density of labelling (values ranging from 3.1 fmol/mg tissue in cervical to 4.5 fmol/mg tissue in lumbar segments). A moderate density (1.8-3.0 fmol/mg tissue) of specific binding was observed in lamina III, whereas in other areas, i.e. laminae I and IV-X, lower amounts of labelling were detected. Within the superficial laminae of the dorsal horn, [125I-Tyr8]bradykinin binding was largely distributed over the neurophil with some perikarya showing concentrations of labelling. In contrast, the ventral horn showed a rather homogeneous distribution of [125I-Tyr8]bradykinin binding over the neuropil, with silver grain alignments surrounding motoneuron perikaryas and proximal processes. Bradykinin, [Tyr8]bradykinin and B2 receptor antagonists (D-Arg[Hyp3,Thi5,D-Tic7,Oic8]bradykinin (Hoe 140), D-Arg[Tyr3,D-Phe7,Leu8]bradykinin, D-Arg[Hyp3, Leu8]bradykinin, D-Arg[Hyp2, Thi5,8,-Phe7]bradykinin D-Arg[Hyp3, D-Phe7, Leu8]bradykinin, Tyr0, D-Arg[Hyp3, D-Phe7, Leu8]bradykinin inhibited [125I-Tyr8]-bradykinin binding with very high subnanomolar affinities, while the B1 receptor agonist (Tyr0,des-Arg10-kallidin) and antagonist ([Leu8]-des-Arg9-bradykinin) did not significantly affect [125I-Tyr8]bradykinin binding at up to micromolar concentrations. Two weeks after unilateral lumbar dorsal rhizotomy (L1-L6) or peripheral lesions of the sciatic nerve, significant decreases ( +/- 50%) in [125I-Tyr8]bradykinin binding sites were found in ipsilateral laminae I-III of lumbar spinal cord.(ABSTRACT TRUNCATED AT 250 WORDS)

Amino Acid Sequence↗
PubMed1996

Induction of transmitter release at the neuromuscular junction prevents motoneuron death after axotomy in neonatal rats.

Motoneurons to rat hindleg muscles die after neonatal nerve injury. Here we show that increasing transmitter release of motor nerve terminals by treatment with 4-aminopyridine, prior to nerve injury at three days, reduces the extent of motoneuron death. Retrograde labelling of soleus motoneurons was carried out in 10-week-old animals that had their sciatic nerve crushed on one side when they were three days old. Only 20% (+/- 4.2 S.E.M.) of the motoneurons survived the nerve injury. A group of animals similarly injured at three days had their calf muscles treated with 4-aminopyridine at birth, prior to nerve injury. In these animals a significantly higher percentage (51 +/- 6.6% S.E.M.) of soleus motoneurons survived. In order to assess the proportion of surviving alpha-motoneurons only, the number of motor units in both the soleus and extensor digitorum longus muscles was established by following the stepwise increments of twitch tension in response to increasing intensity of stimulation of the respective motor nerve. After nerve injury at three days only 18% (+/- 4.1% S.E.M.) of motor units to soleus and 28.5% (+/- 4.9% S.E.M.) to extensor digitorum longus survived and were able to reinnervate their respective muscles. If the nerve injury was preceded by local application of 4-aminopyridine, then the number of motor units present in the reinnervated muscles was significantly greater, so that in soleus 52.7% (+/- 5.4% S.E.M.) and in extensor digitorum longus 52.1% (+/- 2.4% S.E.M.) of motor units were present. This increase of motoneuron survival was reflected in a smaller weight loss and in a better restoration of force production by the pretreated as compared to untreated muscles on reinnervation after nerve injury. It is suggested that enhancing transmitter release from nerve endings in neonatal animals induces the motoneuron to become more resistant to nerve injury.

4-Aminopyridine↗
PubMed1984

Plasticity of catecholaminergic neurons in aged rat brain: reinnervation and functional recovery after axotomy.

Regenerative growth at the lesion site, reinnervation of a target nucleus and functional manifestations of recovery were studied in aged (20 and 30 months old) rats subjected to long-term transection of catecholaminergic (CA) fibers which contact and influence neurons of the supraoptic nucleus (SON). Small bilateral knife cuts were placed stereotaxically just caudal and medial to the SON. CA histofluorescence, induced by formaldehyde-glutaraldehyde (FAGLU) or aluminum-formaldehyde (ALFA) methods, was examined in hypothalamus at 2, 14, 21 and 60 days postsurgically. Water consumption, and urine volume and osmolality, were monitored presurgically, and through survival times. Subtotal CA denervation in the SON, and typical axonal transmitter "pile-up" at the lesion site, were evident two days after surgery. Among these degenerative profiles, which persisted for up to three weeks, fine-sized new fibers were apparent at the lesion, beginning between 2 and 14 days, and persisting throughout the period studied. At 21 days, and progressively thereafter, SON neurons were rimmed with fluorescent varicosites. Water consumption initially was depressed, but returned to presurgical mean levels by nine days. Urine volume returned to normal by 32 days. Urine osmolality showed a recovery by approximately three weeks. These functional parameters rebounded to levels higher than presurgical means among 20 month old, but not 30 month old, rats beyond 6 weeks survival, concurrent with a morphological hyperinnervation. The results reaffirm morphological regeneration, and support reinnervation and functional recovery, which extend considerably into the aging process.

Afferent Pathways↗
PubMed1989

Expression of nerve growth factor receptor mRNA is developmentally regulated and increased after axotomy in rat spinal cord motoneurons.

In situ hybridization histochemistry and RNA blot analysis were used to study expression of nerve growth factor receptor (NGF-R) mRNA in rat spinal cord motoneurons. The results show that NGF-R mRNA is expressed at high levels in rat spinal cord motoneurons at the time of naturally occurring cell death. This expression is sustained, but reduced, during synapse formation and is subsequently greatly reduced in the adult spinal cord. A unilateral crush lesion of the sciatic nerve resulted in an 8-fold increase in NGF-R mRNA in adult rat spinal cord motoneurons 3 days after lesion, compared with the nonlesioned side. NGF-R mRNA induction was even more pronounced 7 and 14 days after lesion, reaching levels 12 times higher than those on the nonlesioned side. However, 6 weeks after lesion, when the motor function of the leg was largely restored, NGF-R expression had decreased to levels similar to those on the contralateral side. We therefore suggest that NGF-R mediates a trophic or axonal guidance function for developing and regenerating spinal cord motoneurons.

Animals↗
PubMed1991

A case for transmitter plasticity at the molecular level: axotomy-induced VIP increase in the upper spinal dorsal horn is related to blockade of retrograde axoplasmic transport of nerve growth factor in the peripheral nerve.

Blockade of retrograde axoplasmic transport in peripheral nerves, by means of perineurally applied microtubule inhibitors, results in an increased vasoactive intestinal polypeptide (VIP) reaction of the segmentally related, ipsilateral upper dorsal horn. Similar effect is elicited by the perineural application of an anti-Nerve Growth Factor (anti-NGF) serum. At the same time, both treatments result in depletion of Substance P from the same region of the spinal cord. It is assumed that this striking example of transmitter plasticity, obviously taking place at the molecular level, is due to a stimulating effect of NGF upon the perikaryal Substance P-synthesizing mechanism in dorsal root ganglion cells, and the inhibitory effect of NGF upon the VIP synthesizing machinery in these same nerve cells.

Animals↗