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PubMed2000

Caspase-3 is activated following axotomy of neonatal facial motoneurons and caspase-3 gene deletion delays axotomy-induced cell death in rodents.

In this report, we examined the possible functions of the cell death protease, caspase-3, in the axotomy-induced apoptosis of facial motoneurons in newborn rodents. Using in situ hybridization and Western blot, we found higher levels of caspase-3 mRNA and pro-caspase-3 protein expression in motoneurons of neonatal and 2-week-old rats than adult rats. Following facial motoneuron axotomy, caspase-3 mRNA and protein expression increased in motoneurons of both neonatal and adult rats. However, using an antibody directed to the activated form of the caspase-3 protease, we found that catalytically active caspase-3 was present only in axotomized neonatal motoneurons. As motoneurons in neonatal but not adult rodents are susceptible to axotomy-induced apoptosis, we hypothesized that caspase-3 may play a role in their demise. To determine the necessity of caspase-3 activation in axotomy-induced apoptosis, we counted the number of surviving motoneurons at 4 and 7 days following axotomy in wild type mice and caspase-3 gene-deleted mice. There were nearly three times more surviving motoneurons in caspase-3 gene-deleted mice than in wild type mice at both 4 days (mean 1074 vs. 464, P<0.005) and 7 days (mean 469 vs. 190, P<0.005) following injury, indicating a slower rate of death. Examination of the dying motoneurons using TUNEL staining (for fragmented DNA) and bisbenzimide staining (for nuclear morphology) revealed incomplete nuclear condensation in caspase-3-deficient motoneurons. These results demonstrate that caspase-3 activation plays important roles in the rapid demise of axotomized neonatal motoneurons.

Age Factors↗
PubMed1983

'Zap axotomy': localized fluorescent excitation of single dye-filled neurons induces growth by selective axotomy.

The response of populations of neurons to axotomy has traditionally been studied by crushing or sectioning whole nerve trunks. The present communication describes a technique by which single neurons can be reliably and selectively axotomized in the absence of damage to other axons and non-neuronal cells within the nerve. To obtain selective axotomy, identified neurons of the buccal ganglia of the snail, Helisoma, were first filled with fluorescent dye. Next, the preparation was positioned in a restricted beam of blue light using low light video fluorescence microscopy. Finally, the selected region of axon was briefly exposed to light levels normally employed for fluorescence microscopy. Shortly after irradiation of the identified neuron 5, antidromic action potentials no longer propagated past the region of exposure in the dye-filled cell, whereas adjacent axons were physiologically intact. Several days after exposure, profuse neurite outgrowth was observed from the proximal region of axon of neuron 5, but never in neighboring axons which were not filled with dye at the time of irradiation. When the axons of both neurons 5R and 5L were spot irradiated neurite outgrowth resulted in the formation of a novel electrical connection between these cells. These changes in growth and connectivity which were induced by selective axotomy of single axons were indistinguishable from the changes which are produced by crushing entire nerve trunks.

Animals↗
PubMed1988

Neurofilament protein synthesis in DRG neurons decreases more after peripheral axotomy than after central axotomy.

Cytoskeletal protein synthesis was studied in DRG neurons after transecting either their peripheral or their central branch axons. Specifically, the axons were transected 5-10 mm from the lumbar-5 ganglion on one side of the animal; the DRGs from the transected side and contralateral control side were labeled with radiolabeled amino acids in vitro; radiolabeled proteins were separated by 2-dimensional (2D) PAGE; and the amounts of radiolabel in certain proteins of the experimental and control ganglia were quantified and compared. We focused on the neurofilament proteins because they are neuron-specific. If either the peripheral or central axons were cut, the amounts of radiolabeled neurofilament protein synthesized by the DRG neurons decreased between 1 and 10 d after transection. Neurofilament protein labeling decreased more after transection of the peripheral axons than after transection of the central axons. In contrast to axonal transections, sham operations or heat shock did not decrease the radiolabeling of the neurofilament proteins, and these procedures also affected the labeling of actin, tubulin, and the heat-shock proteins differently from transection. These results and others indicate that axonal transection leads to specific changes in the synthesis of cytoskeletal proteins of DRG neurons, and that these changes differ from those produced by stress to the animal or ganglia. Studies of the changes in neurofilament protein synthesis from 1 to 40 d after axonal transection indicate that the amounts of radiolabeled neurofilament protein synthesis were decreased during axonal elongation, but that they returned toward control levels when the axons reached cells that stopped elongation.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1981

Ionic and metabolic dependence of axotomy-induced somatic membrane changes in crayfish.

1. Axotomy induces a transient change in the soma membrane from non-spiking to spiking in many neurones of the crayfish abdominal C.N.S. The ionic and metabolic dependence of this phenomenon was investigated in one identified neurone. 2. The inward current of axotomy-induced soma spikes is carried primarily by Na ions. 3. Addition of 50 mM-tetraethylammonium to the external saline unmasks predominantly Ca-mediated soma spikes in control cells. The calcium spikes are not affected by axotomy. 4. Axotomy induces a transient increase in delayed rectification of the soma membrane. 5. Membrane potential is dependent on the external potassium concentration as predicted by the Nernst function while external sodium has essentially no effect. This is not changed following axotomy. 6. The inward current of the axon spike is primarily carried by sodium ions both before and after axotomy. The overshoot of the axon spike is not dramatically changed between the time when axotomy-induced soma spikes are present and when they have disappeared. 7. Following axotomy, both the onset and offset of axotomy-induced soma spikes occur earlier when the temperature is raised by 10 degrees C. 8. Cycloheximide retards or prevents soma spikes normally seen following axotomy. 9. The results indicate that axotomy induces a transient increase in voltage-dependent Na and K conductances but not Ca conductance, and that these changes are dependent on axotomy-inhibited protein synthesis.

Action Potentials↗
PubMed1999

Reciprocal changes in the expression of Bcl-2 and Bax in hypoglossal nucleus after axotomy in adult rats: possible involvement in the induction of neuronal cell death.

Numerous studies of neonatal neuronal development in mammals have revealed that neuronal cell death following axotomy is apoptotic in nature. In adult animals, however, neuronal cell death following axonal injury may or may not exhibit features of apoptosis. Bcl-2 and Bax have been identified as inhibitor and promoter proteins, respectively, of apoptosis. To investigate the relationship between these proteins and neuronal cell death following axotomy in adult animals, we performed axotomy of the right hypoglossal nerve in adult male Wistar rats, and sacrificed the rats at various intervals after axotomy. We analyzed the expression of Bcl-2 and Bax immunohistochemically in the hypoglossal nuclei of the adult rats following axotomy. Our analysis showed an increase in the percentage of Bax-positive motoneurons relative to the total number of motoneurons in the hypoglossal nucleus on the axotomy side at three days after axotomy. In contrast, a low percentage of Bcl-2-positive motoneurons to the total number of motoneurons was noted at the same time interval after axotomy. Quantitative analysis of the signal intensity for Bcl-2 and Bax in individual neurons showed that Bax immunostaining significantly increased 7 days after axotomy, while the intensity of Bcl-2 immunostaining decreased in most of Bcl-2-positive neurons. Our results confirmed the occurrence of motoneuron cell death in adult rats after axotomy, and that a close temporal relationship exists between the reciprocal changes in Bcl-2/Bax expression and the loss of motoneurons. These results indicate the possible involvement of the Bcl-2/Bax system in the induction of neuronal cell apoptosis after axotomy in adult rats.

Age Factors↗
PubMed1991

Response of facial and rubrospinal neurons to axotomy: changes in mRNA expression for cytoskeletal proteins and GAP-43.

Neurons confined within the mammalian CNS usually do not regenerate after axonal injury, while axonal regeneration is the rule in the PNS. It has been hypothesized that this may be related to differences in the microenvironment of the PNS versus CNS and to differences in the neuronal response to injury. In order to test the latter hypothesis, we compared changes in gene expression after axotomy in two populations of neurons: rat facial motoneurons and rat rubrospinal neurons. In situ hybridization with cDNA probes for the medium and light neurofilament protein revealed a reduced mRNA content in both facial and rubrospinal neurons at all times investigated (i.e., 1, 2, and 3 weeks after axotomy). On the other hand, mRNAs for actin and tubulin were increased in both neuronal populations during the first week after axotomy. While this increase was sustained in facial motoneurons for several weeks, total tubulin mRNA and actin mRNA were decreased in rubrospinal neurons at 2 and 3 weeks after axotomy, coincident with their atrophy. The developmentally regulated T alpha 1 tubulin mRNA, which was previously shown to be reexpressed in facial motoneurons after axotomy, was elevated severalfold in axotomized rubrospinal neurons, and increased levels persisted in some rubrospinal neurons as late as 7 weeks after axotomy. Similarly, the developmentally regulated GAP-43 mRNA increased in both axotomized facial and rubrospinal neurons, and increased levels were sustained in some axotomized rubrospinal neurons for at least 7 weeks. The response of rubrospinal neurons to axotomy in the cervical spinal cord is, in the first week, qualitatively similar to the response of facial motoneurons. However, by 2 weeks after axotomy there is a generalized reduction in mRNA levels for all three cytoskeletal proteins that is associated with neuronal atrophy. During this period, mRNA levels for the two specific markers of the growth state, T alpha 1 tubulin and GAP-43, remain elevated. Thus, axotomy of rubrospinal neurons appears to set in motion two independent events. First, an axotomy signal initiates a cell-body reaction similar to that of PNS neurons, including increased mRNA levels for T alpha 1 tubulin and GAP-43. Later, a generalized cellular atrophy and decrease in mRNA levels occur without reversing the specific responses of T alpha 1 and GAP-43 to axotomy. We conclude that the failure of rubrospinal neurons to regenerate is not due to a failure to initiate gene-expression changes characteristic of regenerating peripheral neurons.(ABSTRACT TRUNCATED AT 400 WORDS)

Actins↗
PubMed1990

Cell death of corticospinal neurons is induced by axotomy before but not after innervation of spinal targets.

The response of corticospinal neurons to axotomy at postnatal ages from 5 days to adulthood was studied in the golden hamster (Mesocricetus auratus). Corticospinal neurons were retrogradely labeled with fluorescent rhodamine latex beads injected into the cervical or lumbar spinal cord. A unilateral lesion of the medullary pyramidal tract was made 1-2 days later and the brains fixed 1-30 days after axotomy. Comparisons of labeled axotomized corticospinal neurons with labeled normal corticospinal neurons in the contralateral cortex showed that axotomy at 14 days or later caused cell shrinkage but not cell death. Axotomy prior to 14 days caused cell death of corticospinal neurons. More neurons died the earlier the lesion was made, culminating in virtual complete cell death of corticospinal neurons following axotomy at 5 days. Axotomy at a given age did not affect all corticospinal neurons uniformly. Lumbar projection neurons underwent cell death ranging from slight to complete following axotomy at 13 and 9 days, respectively. Cervical projection neurons, in contrast, survived axotomy after a lesion at 9 days but underwent complete cell death if the lesion occurred at 5 days. Since corticospinal axons innervate the cervical cord from postnatal days 4-8 and the lumbar cord from 10-14 days (Reh and Kalil, '81; J. Comp. Neurol. 200:55-67), the ability of corticospinal neurons to survive axotomy appears to be temporally well correlated with their innervation of spinal targets. These neurons die if their axons are cut prior to target innervation but are able to survive if axotomy occurs after their axons innervate spinal targets. The results show that plasticity in the corticospinal pathway documented in previous reports cannot take the form of regrowth of severed axons, since early lesions cause extensive corticospinal cell death. Aberrant corticospinal pathways resulting from early lesions must therefore arise from undamaged axons. Additional retrograde labeling experiments showed that the opposite cortex responded to contralateral pyramidotomy by sprouting into denervated areas of the spinal cord. Thus another source of plasticity after early pyramidal tract lesions is sprouting from corticospinal axons arising from the intact cortex.

Aging↗
PubMed1996

Interleukin-1 involvement in the induction of leukemia inhibitory factor mRNA expression following axotomy of sympathetic ganglia.

Axotomy of superior cervical (sympathetic) ganglia (SCG) results in increased neuropeptide gene expression. In vitro, neuropeptide gene expression is similarly increased by exposure to the inflammatory cytokine interleukin-1 (IL-1). The effect of IL-1 in-vitro has been shown to be mediated by leukemia inhibitory factor (LIF). Since IL-1 regulates neuropeptide expression via LIF in vitro, we asked whether axotomy in vivo produces an increase in LIF mRNA, and whether that increase is regulated by IL-1 activity. Within 6 h following axotomy, ganglionic LIF mRNA is substantially elevated. Moreover, axotomy produces a rapid and transient increase in intraganglionic IL-1 beta mRNA, followed rapidly by an increase in ICAM-1 mRNA, thereby suggesting a local source of IL-1 activity. Pretreatment with the anti-inflammatory agent dexamethasone (DEX) reduces the increases of both IL-1 beta and LIF mRNAs following axotomy. mRNA encoding the specific signal-transducing Type I IL-1 receptor is present in unlesioned SCG in vivo, and increases following axotomy. Local application of IL-1 beta in vivo induces LIF mRNA even in uninjured ganglia, though not to the extent seen with axotomy. DEX treatment blocks this IL-1 beta-mediated increase in LIF mRNA. Therefore, DEX blocks the induction of LIF mRNA by inhibiting both the production of IL-1 and its action on LIF gene expression. Axotomy of a homozygous IL-1 receptor type I gene knockout mouse leads to a delayed and/or diminished induction of LIF mRNA in SCG, but does not prevent LIF mRNA expression. We conclude that while IL-1 is likely to be involved in the cascade of gene expression that follows axotomy, it alone is not sufficient to mediate the full induction of LIF mRNA by axotomy.

Animals↗
PubMed1987

Effects of central or peripheral axotomy on membrane properties of sensory neurones in the petrosal ganglion of the cat.

1. The properties of sensory neurones in the petrosal ganglion of the cat were examined in vitro with intracellular electrodes 8 days after section of the central (bulbar roots) or peripheral process. Two types of cells, both with conduction velocities faster than 2 m/s and with humps on the falling phases of their action potentials (H-neurones), were studied: glossopharyngeal neurones arising from the tongue and pharynx, and carotid neurones originating in the carotid body and carotid sinus. 2. Peripheral axotomy produced an increase in action potential duration and a marked decrease in the amplitude and duration of the spike after-hyperpolarization in both glossopharyngeal and carotid neurones. 3. The maximum rate of depolarization of the action potential increased after peripheral axotomy in glossopharyngeal cells but did not change in carotid neurones. 4. The time-dependent inward rectification in response to hyperpolarizing pulses was markedly reduced in both types of cells after peripheral axotomy. 5. Section of the peripheral process produced a decrease of the rheobase of glossopharyngeal cells, but not of carotid neurones. After axotomy the proportion of cells giving tonic discharges in response to long depolarizing pulses increased from 13 to 54% among carotid neurones but did not change in glossopharyngeal cells. 6. No significant changes in membrane potential or input resistance of either group of cells were found after peripheral axotomy. 7. Central axotomy did not produce any changes in the electrophysiological properties of glossopharyngeal or carotid neurones. 8. Peripheral conduction velocity was decreased in both types of cells after peripheral axotomy, but did not change after section of the bulbar roots. 9. It is concluded that the electrical properties of sensory neurones are modified after peripheral axotomy but not after central axotomy. Furthermore, the changes produced by peripheral axotomy are different in neurones innervating different peripheral targets. 10. The possibility that some electrical properties of sensory neurones are maintained by their peripheral targets is discussed.

Action Potentials↗
PubMed1993

Changes in sodium and calcium channel activity following axotomy of B-cells in bullfrog sympathetic ganglion.

1. Currents mediated by Ca2+ channels using Ba2+ as a charge carrier (IBa), Na+ currents (INa) and voltage- and Ca(2+)-dependent K+ currents (IC) were recorded from bullfrog paravertebral sympathetic ganglion B-cells using whole-cell patch-clamp recording techniques. Currents recorded from control cells were compared with those from axotomized cells 13-15 days after transection of the postganglionic nerve. 2. Axotomy reduced peak IBa at -10 mV (holding potential = -80 mV) from 3.3 +/- 0.3 nA (n = 42) to 1.7 +/- 0.1 nA (n = 39, P < 0.001). Tail IBa at -40 mV following a step to +70 mV from a holding potential of -80 mV was also reduced in axotomized neurones (9.7 +/- 0.6 nA for forty-two control neurones and 5.2 +/- 0.3 nA for thirty-nine axotomized neurones; P < 0.001). Minimal changes were observed in the kinetics of activation and deactivation. 3. Pharmacological experiments using 1,4-dihydro-2,6-dimethyl-3-nitro-4-(2- trifluoromethylphenyl)-pyridine-5-carboxylic acid methyl ester (BayK 8644), nifedipine and omega-conotoxin showed that axotomy predominantly affected the N-type Ca2+ channels which carry the majority of ICa in these neurones. L-type Ca2+ current was little affected and T-type Ca2+ currents were not observed in control or axotomized cells. 4. Development of inactivation of 0 mV and recovery from inactivation of IBa at -80 mV exhibited three distinct components in both control and axotomized neurones: 'fast', 'intermediate' and 'slow'. The relative proportions of both the 'fast' and 'intermediate' components of inactivation at 0 mV were almost doubled after axotomy (fast component was 15% in control and 29% in axotomized neurones; intermediate component was 17% in control and 26% in axotomized neurones). 'Fast' and 'intermediate' inactivation tended to develop more rapidly and recover more slowly after axotomy. The rate of onset of 'slow' inactivation was unaffected by axotomy but the steady-state level at -40 mV was increased. Most of the change in IBa properties may be secondary to enhanced inactivation associated with axotomy. 5. Axotomy reduced IC (measured at the end of a 3 ms step from -40 to +20 mV) from 34.5 +/- 4.9 (n = 26) to 19.2 +/- 1.5 nA (n = 49, P < 0.005). This reduction may be secondary to the reduction in calcium channels available for activation from -40 mV following axotomy. 6. The TTX-sensitive and TTX-insensitive components of peak Na+ conductance (GNa) were both increased after axotomy. Total GNa was increased from 184.9 +/- 8.4 to 315.2 +/- 16.4 nS (n = 37 for both P < 0.001). Most of the kinetic and steady-state properties of INa were unchanged after axotomy.(ABSTRACT TRUNCATED AT 400 WORDS)

3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethy↗
PubMed1991

Axotomy alters putative neurotransmitters in visceral sensory neurons of the nodose and petrosal ganglia.

Acute peripheral axotomy of the visceral sensory neurons of the vagus and glossopharyngeal nerves removes peripheral depolarizing and trophic influences to their sensory ganglia. To study axotomy-induced changes in the putative neurotransmitters of visceral sensory neurons, rats were sacrificed 1, 3, 7 or 14 days after transection of either the cervical vagus and superior laryngeal nerves (to affect peripheral axotomy of the nodose ganglion) or the glossopharyngeal and carotid sinus nerves (to affect peripheral axotomy of the petrosal ganglion). The numbers of tyrosine hydroxylase (TH)-immunoreactive (ir), vasoactive intestinal peptide (VIP)-ir, calcitonin-gene-related peptide (CGRP)-ir, and substance P (SP)-ir neurons in the respective ganglia were analyzed in axotomized and control ganglia. In the nodose ganglion, axotomy of the cervical vagus resulted in a rapid (by 1 day) reduction in the number of TH-ir cells, whereas VIP-ir neurons were dramatically increased in number by 3 days. CGRP- and SP-ir cells in the nodose ganglion were relatively unaffected by axotomy. In the petrosal ganglion, axotomy of the glossopharyngeal and carotid sinus nerves greatly reduced the number of TH-ir cells but did not alter the number VIP-ir neurons. CGRP- and SP-ir neurons in the petrosal ganglion were reduced in number by axotomy. Thus, axotomy of visceral sensory neurons differentially changed the content and perhaps the expression of putative transmitters. Differential changes were seen among transmitters in a single ganglia and between ganglia. These data demonstrate the plasticity of putative neurotransmitter systems in visceral afferent systems of adult rats.

Animals↗
PubMed1994

Naturally occurring and axotomy-induced motoneuron death and its prevention by neurotrophic agents: a comparison between chick and mouse.

Neuronal cell death is an important regressive event during the normal development of the peripheral and central nervous systems of many vertebrate and invertebrate species. Furthermore, when neurons are deprived of their target following axonal injury (axotomy) during embryonic, fetal, or early postnatal development, they undergo massive cell death. Both naturally occurring and axotomy-induced neuronal cell death can be prevented by treatment with growth factors or neurotrophic agents. Naturally occurring cell death of spinal MNs has been extensively studied in both avians and mammals. However, compared with mammals, there is little information on the effects of axotomy in avian species and it is not known whether trophic agents can modify axotomy-induced death in avian MNs. It is also not known whether trophic/growth factors can promote the in vivo survival of mammalian MNs during the period of naturally occurring cell death. We have examined (1) the time course of axotomy-induced death of lumbar spinal MNs in chick and mouse, and (2) the survival-promoting activity of a number of previously characterized growth and trophic factors on both programmed and axotomy-induced MN death in these two species. We show that axotomy performed on, or prior to, E12 in the chick results in a rapid decrease (i.e. 50%) in MN numbers within 3-4 days postsurgery, whereas these cells were able to survive for up to 1 week following axotomy on E14. By contrast, mouse MNs remained vulnerable to axotomy for at least 5 days after birth.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1997

The effects of remaining axons on motoneuron survival and NOS expression following axotomy in the adult rat.

it is well known that target removal or distal axotomy in adult animals results in no detectable loss of motoneurons in the spinal cord. By performing axotomy in the seventh cervical (C7) spinal nerve at different distances from the spinal cord (0, 2, 4, 8 mm respectively), this study examines the effects of the remaining axons on motoneuron survival as well as NOS expression. Results of the present study show that axotomy in adult peripheral nerve can induce significant spinal motoneuron death if axotomy is performed close enough to the spinal cord. The closer the axotomy to the spinal cord, the higher the rate of motoneuron loss was observed. The most significant motoneuron loss was found in animals with axotomy at 0 mm to the cord, which was coincident with the highest percent of NOS-positive motoneurons. The rate of survival of motoneurons increases and the percent of NOS-positive motoneurons decreases when the distance of the axotomy to the cord increases from 0 to 4 mm. No significant motoneuron loss nor NOS-positive motoneurons were observed when axotomy was performed at 4 mm and distally. These results indicate that the survival of spinal motoneurons in adult rat following axotomy is largely dependent on the length of the remaining axons. The longer the remaining axon, the better for motoneuron survival. The minimal length of axon for motoneuron survival in adult rat seems to be at least 4 mm.

Animals↗
PubMed2001

Axotomy- and autotomy-induced changes in Ca2+ and K+ channel currents of rat dorsal root ganglion neurons.

Sciatic nerve section (axotomy) increases the excitability of rat dorsal root ganglion (DRG) neurons. The changes in Ca2+ currents, K+ currents, Ca2+ sensitive K+ current, and hyperpolarization-activated cation current (I(H)) that may be associated with this effect were examined by whole cell recording. Axotomy affected the same conductances in all types of DRG neuron. In general, the largest changes were seen in "small" cells and the smallest changes were seen in "large" cells. High-voltage-activated Ca2+ channel current (HVA-I(Ba)) was reduced by axotomy. Although currents recorded in axotomized neurons exhibited increased inactivation, this did not account for all of the reduction in HVA-I(Ba). Activation kinetics were unchanged, and experiments with nifedipine and/or omega-conotoxin GVIA showed that there was no change in the percentage contribution of L-type, N-type, or "other" HVA-I(Ba) to the total current after axotomy. T-type (low-voltage-activated) I(Ba) was not affected by axotomy. Ca2+ sensitive K+ conductance (g(K,Ca)) appeared to be reduced, but when voltage protocols were adjusted to elicit similar amounts of Ca2+ influx into control and axotomized cells, I(K,Ca)(s) were unchanged. After axotomy, Cd2+ insensitive, steady-state K+ channel current, which primarily comprised delayed rectifier K+ current (I(K)), was reduced by about 60% in small, medium, and large cells. These data suggest that axotomy-induced increases in excitability are associated with decreases in I(K) and/or decreases in g(K,Ca) that are secondary to decreased Ca2+ influx. Because I(H) was reduced by axotomy, changes in this current do not contribute to increased excitability. The amplitude and inactivation of I(Ba) in all cell types was changed more profoundly in animals that exhibited self-mutilatory behavior (autotomy). The onset of this behavior corresponded with significant reduction in I(Ba) of large neurons. This finding supports the hypothesis that autotomy, that may be related to human neuropathic pain, is associated with changes in the properties of large myelinated sensory neurons.

Animals↗
PubMed1992

Axonal regeneration of an identified Helisoma neuron depends on the site of axotomy.

Axotomy of molluscan neurons usually results in axonal regeneration. In this study, we tested the axotomy response of an identified neuron of the pond snail Helisoma trivolvis (buccal neuron 4, B4). This neuron has two primary axonal branches, the ipsilateral axon and the contralateral axon, each innervating one of the paired salivary glands. The ipsilateral axon projects via the ipsilateral esophageal nerve trunk whereas the contralateral axon crosses both buccal ganglia and projects via the contralateral esophageal nerve trunk. We tested various procedures of axotomy: injury to one axon or both axons, close to the ganglion or more distal. Surprisingly, we found that proximal axotomy of the ipsilateral axon was not usually followed by axonal regeneration. By contrast, all other procedures of axotomy (e.g., distal ipsilateral, or proximal bilateral) resulted in robust axonal regeneration and target reinnervation. Thus, in this preparation, axotomy may or may not result in axonal regeneration, depending on the site(s) of axotomy. To the best of our knowledge, such a differential result has not yet been found in any other preparation. We conclude that axotomy is not always a sufficient condition for axonal regeneration of molluscan neurons. We hypothesize that a damaged axonal stump may be a necessary condition for the initiation of regeneration. An alternative hypothesis is that neurite outgrowth is inhibited in normal mature neurons by a target-derived factor. This hypothetical factor would be transported retrogradely, but not anterogradely, along axons.

Animals↗
PubMed1984

Fast axonal transport in central nervous system and peripheral nervous system axons following axotomy.

After axotomy, changes in the composition of fast axonally transported proteins ( FTP ) within the peripheral nervous system (PNS) axons have been reported. The most significant and reproducible changes involved polypeptides found within the molecular weight range of 31.0 to 14.5 kilodaltons ( Bisby , 1980). We wished to determine whether similar changes following axotomy occur in axons of the central nervous system (CNS). Intracranial axotomy of the left optic tract was performed stereotaxically in rats. Six days post axotomy 50 muCi 35[S]-methionine was injected into the vitreous body of both eyes. FTP were isolated within the optic nerves 2 h after isotope injection. The nerve segments were processed for SDS-PAGE, fluorography, and compared to similarly prepared fluorographs of normal and eight day post-axotomy sciatic nerve segments. The labelling of 5 major polypeptide bands (S1, MW congruent to 28,000; S2a , MW congruent to 25,000; S2b , MW congruent to 23,000; T1, MW congruent to 20,200; and T2, MW congruent to 17,000) was studied by laser densitometry. Band S2b showed a highly significant (p less than 0.001) increase in concentration, while bands S1 and T1 demonstrated highly significant decreases in concentration following axotomy of the sciatic nerve. In contrast, after axotomy of the retinal ganglion cell axons the only significant change was a decrease (p less than 0.05) in T1. We suggest that failure of CNS axons to respond similarly to PNS axons following axotomy may be related to the failure of CNS axons to regenerate.

Animals↗
PubMed1995

Axotomy of developing rat spinal motoneurons: cell survival, soma size, muscle recovery, and the influence of testosterone.

During the period of synapse elimination, motoneurons are impaired in their ability to generate or regenerate axonal branches: following partial denervation of their target muscle, young motoneurons do not sprout to nearby denervated fibers and after axonal injury, they fail to reinnervate the muscle. In the rat levator ani (LA) muscle, which is innervated by motoneurons in the spinal nucleus of the bulbocavernosus (SNB), synapse elimination ends relatively late in development and can be regulated by testosterone. We took advantage of this system to determine if the end of synapse elimination and the development of regenerative capabilities by motoneurons share a common mechanism, or, alternatively, if these two events can be dissociated in time. Axotomy on or before postnatal day 14 (P14) caused the death of SNB motoneurons. By P21, toward the end of synapse elimination in the LA muscle, SNB motoneurons had developed the ability to survive axonal injury. Altering testosterone levels by castration on P7 followed by 4 weeks of either testosterone propionate or control injections did not change the ability of SNB motoneurons to survive axonal injury during development, although these same treatments alter the time course of synapse elimination in the LA muscle. Thus, we dissociated the inability of SNB motoneurons to recover from axonal injury from their developmental elimination of synaptic terminals. We also measured the effect of early axotomy on motoneuronal soma size and on target muscle weight. Axotomy on P14 caused a long-lasting decrease in the soma size of surviving SNB motoneurons, whereas motoneurons axotomized on P28 recovered their normal soma size. Axotomy on or before P7 caused severe atrophy of the target muscles, matching the extensive loss of motoneurons. However, target muscle recovery after axotomy on P14 was as good as recovery after axotomy at later ages, despite greater motoneuronal death after axotomy on P14. This result may reflect an increase in motor unit size, a decrease in polyneuronal innervation by SNB motoneurons that survive axotomy on P14, or a combination of the two.

Animals↗
PubMedDate not supplied

Long-term effects of axotomy on beta-tubulin and NF gene expression in rat DRG neurons.

To compare the long-term recovery of gene expression in dorsal root ganglion (DRG) neurons under conditions of regeneration vs. non-regeneration, Northern blotting and in situ hybridization were used to assess steady-state neurofilament (NF) and beta tubulin mRNA levels 12 weeks following axonal injury. Adult male rats sustained either a crush lesion of the mid-sciatic nerve (regeneration occurs), or a cut lesion of the sciatic nerve combined with ligation of the proximal nerve stump and removal of a large segment of the distal nerve (regeneration does not occur). In the latter case, neuroma formation physically prevented axonal regeneration. Results of Northern blotting of total RNA obtained from the DRG indicated that NF-L and NF-M mRNA levels had largely returned to control levels at 12 weeks following crush axotomy but were still substantially depressed following cut/ligation injury of the sciatic nerve at that time. In situ hybridization studies indicated that both crush and cut/ligation axotomy resulted in significantly lower NF-L mRNA levels in large-sized (> 1000 micron2) DRG neurons at 12 weeks post-axotomy. Discrepancies in the conclusions from Northern blotting and in situ hybridization experiments were also noted in the case of tubulin mRNA changes at long intervals after axotomy. In situ hybridization data derived from the large-sized DRG neurons using a coding region beta-tubulin cDNA (which recognizes both beta II and beta III mRNAs) showed complete recovery of beta-tubulin mRNA levels in surviving large-sized DRG neurons after crush axotomy, but significantly elevated tubulin mRNA levels in surviving large DRG cells at 12 weeks after cut/ligation axotomy. In contrast, Northern blotting results indicated that beta II-tubulin mRNA levels in the crush axotomy condition remained elevated relative to control while they were substantially lower than control in cut/ligation axotomy samples. Results from analysis of beta III-tubulin mRNA changes were not conclusive. The lack of complete correspondence in the results from the two different methods of analysis of mRNA changes (blotting vs. in situ) is likely to be due to selective loss of large-sized DRG neurons in the long-standing cut/ligation injury condition. This would influence results from blotting data, where RNA is derived from the DRG as a whole, more so than in situ hybridization experiments which specifically focus on the surviving large-sized neurons. Overall, data from these experiments indicate that altered patterns of gene expression remain in the DRG for long intervals after axonal injury, whether or not axonal regeneration has been successful.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗