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PubMed2005

Modulation of the glutamatergic receptors (AMPA and NMDA) and of glutamate vesicular transporter 2 in the rat facial nucleus after axotomy.

Facial nerve axotomy is a good model for studying neuronal plasticity and regeneration in the peripheral nervous system. We investigated in the rat the effect of axotomy on the different subunits of excitatory glutamatergic AMPA (GLuR1-4), NMDA (NR1, NR2A-D) receptors, post-synaptic density 95, vesicular glutamate transporter 2, beta catenin and cadherin. mRNA levels and/or protein production were analyzed 1, 3, 8, 30 and 60 days after facial nerve axotomy by in situ hybridization and immunohistofluorescence. mRNAs coding for the GLuR2-4, NR1, NR2A, B, D subunits of glutamatergic receptors and for post-synaptic density 95, were less abundant after axotomy. The decrease began as early as 1 or 3 days after axotomy; the mRNAs levels were lowest 8 days post-lesion, and returned to normal or near normal 60 days after the lesion. The NR2C subunit mRNAs were not detected in either lesioned or intact facial nuclei. Immunohistochemistry using specific antibodies against GLuR2-3 subunits and against NR1 confirmed this down-regulation. There was also a large decrease in vesicular glutamate transporter 2 immunostaining in the axotomized facial nuclei at early stages following facial nerve section. In contrast, no decrease of NR2A subunit and of post-synaptic density 95 could be detected at any time following the lesion. beta Catenin and cadherin immunoreactivity pattern changed around the cell body of facial motoneuron by day 3 after axotomy, and then, tends to recover at day post-lesion 60 days. Therefore, our results suggest a high correlation between restoration of nerve/muscle synaptic contact, synaptic structure and function in facial nuclei. To investigate the mechanisms involved in the change of expression of these proteins following axotomy, the facial nerve was perfused with tetrodotoxin for 8 days. The blockade of action potential significantly decreased GLuR2-3, NR1and NR2A mRNAs in the ipsilateral facial nuclei. Thus, axotomy-induced changes in mRNA abundance seemed to depend partly on disruption of activity.

Animals↗
PubMed2004

Absence of an association between axotomy-induced changes in sodium currents and excitability in DRG neurons from the adult rat.

It is generally believed that nerve injury results in neuronal hyperexcitability that reflects in part a change in Na+ currents. However, there are conflicting data on the nature of Na+ current changes and the association between alterations in Na+ currents and increases in excitability. One potential source of conflicting data is that injured and spared neurons may respond differently to nerve injury; these subpopulations of neurons have not been distinguished in previous studies with the axotomy model of nerve injury (complete transection of the sciatic nerve). The present study was performed to determine the relationship between changes in Na+ channels and changes in neuronal excitability in identified injured dorsal root ganglion neurons post-axotomy. Small (< 45 pF) neurons labeled with a DiI injection into the sciatic nerve were studied 10 days and 4 weeks post-axotomy. Ten days post-axotomy, tetrodotoxin-resistant (TTX-R) Na+ current (INa) was decreased and TTX-sensitive (TTX-S) INa was increased, however, excitability was unchanged. Four weeks post-axotomy, neurons had become hyperexcitable while TTX-R INa remained reduced and TTX-S INa had returned to control levels. Thus, axotomy-induced changes in Na+ currents were not correlated with an axotomy-induced change in excitability. Additional analysis of axotomized neurons suggested that concomitant changes in other ionic currents occurred. These results suggest that neuronal excitability following axotomy is dependent on the sum of changes in ionic currents, and the overall effect on excitability may not always correspond to that predicted by a change in a single class of voltage-gated ion channel.

Action Potentials↗
PubMed2003

Endogenous expression of inhibitor of apoptosis proteins in facial motoneurons of neonatal and adult rats following axotomy.

The inhibitor of apoptosis protein family members inhibit cell death resulting from a variety of apoptotic stimuli. However, the endogenous expression of neuronal inhibitor of apoptosis proteins following axonal injury has not been thoroughly examined. Neonatal facial motoneurons are highly susceptible to axotomy-induced apoptosis, whereas adult facial motoneurons survive axotomy. We hypothesized that the endogenous expression of inhibitor of apoptosis proteins may be involved in the differential susceptibility of adult and neonatal facial motoneurons to axonal injury. In this study, we examined the expression of two endogenous inhibitor of apoptosis proteins, neuronal apoptosis inhibitory protein and x-linked inhibitory apoptosis protein, in adult and neonatal rat facial motoneurons following axotomy. Analyses using reverse-transcription polymerase chain reaction and in situ hybridization indicated that neuronal apoptosis inhibitory protein mRNA was increased in neonatal facial nuclei 24 h post axotomy. In the adult, neuronal apoptosis inhibitory protein mRNA expression increased at 1, 3, 7 and 14 days post axotomy, while little change in the expression of X-linked inhibitory apoptosis protein mRNA was detected at any age or time point time point analyzed. Interestingly, immunohistochemistry using antibodies for neuronal apoptosis inhibitory protein and X-linked inhibitory apoptosis protein, revealed the level of these proteins was higher in the neonatal motoneurons when compared with the adult. Furthermore, immunohistochemistry and western blot for neuronal apoptosis inhibitory protein revealed, in contrast to the observed increase in neuronal apoptosis inhibitory protein mRNA, a decline in the expression of neuronal apoptosis inhibitory protein following axotomy in the adult, whereas no change in neuronal apoptosis inhibitory protein was detected in neonatal facial motoneurons. X-linked inhibitory apoptosis protein, as analyzed by immunohistochemistry and western blot, remained unchanged by axotomy in neonatal motoneurons and adult motoneurons. These results indicate differential expression and/or turnover of inhibitor of apoptosis proteins in neonatal versus adult facial motoneurons, and suggest the level of inhibitor of apoptosis protein expression alone is not an indicator of cell fate following axotomy.

Animals↗
PubMed2002

Fate of the soma and dendrites of cord-projection central neurons after proximal and distal spinal axotomy: an intracellular dye injection study.

We used rat rubrospinal neurons as a model to study the soma-dendritic morphology of cord-projection neurons following spinal axonal injury. We examined lumbar-projection neurons following both upper cervical and lower thoracic axotomy to find out whether changes were dependent on the proximity of the lesion to the cell body. Axotomized neurons were marked with retrograde tracer and studied 4 and 8 weeks later with intracellular dye injection technique. Axotomy resulted in prominent shrinkage of their soma and relatively minor reduction of their dendritic spreads. The degree of soma shrinkage depended on both the duration of survival and the proximity of lesion. In addition, dendritic modification peaked 4 weeks following proximal lesion, which was also achieved 8 weeks following distal axotomy. Tractotomy at upper cervical and lower thoracic levels also allowed us to compare the effect of distal axotomy on cervical and lumbar-projection neurons. Results show that although cervical-projection neurons responded more quickly than lumbar-projecting ones, they however showed a similar degree of alteration in both their soma and dendrites 8 weeks following distal axotomy. In summary, cord-projection neurons survived 8 weeks following either upper cervical or lower thoracic axotomy with relatively intact dendritic features. Taken together, our data thus far suggest that cord-projection central neurons continue to integrate inputs and control supraspinal targets following spinal axotomy. The minor dendritic shrinkage within two months of spinal axotomy rejuvenates hopes for functional recovery if regeneration of their spinal axons can be achieved at least within this time frame.

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↗
PubMed1996

Effects of axotomy and intraocular administration of NT-4, NT-3, and brain-derived neurotrophic factor on the survival of adult rat retinal ganglion cells. A quantitative in vivo study.

PURPOSE: To investigate in vivo the survival of retinal ganglion cells (RGC) 4 to 14 days after optic nerve (ON) transection alone or in combination wih a single intraocular injection of neurotrophin-4 (NT-4), neurotrophin-3 (NT-3), or brain-derived neurotrophic factor (BDNF). METHODS: In adult rats, RGCs were labeled with fluorogold (FG) applied to their main targets in the brain. Seven days later, the left ON was intraorbitally transected, and, in several groups of animals, the left eye received a sham injection or was injected with 5 microliters of 1% bovine serum albumin-phosphate-buffered saline alone or containing 5 micrograms of NT-4, NT-3, or BDNF. Four, 5, 7, 9, 12 and 14 days after ON transection, the retinas were examined under fluorescence microscopy to estimate RGC survival. RESULTS: In control retinas, the mean densities (cells/mm2+/-SEM) of FG-labeled RGCs were 2421+/-55 (n=20). Four days after axotomy, the densities of RGCs were similar to those observed in control retinas, but 5 and 7 days after axotomy, the mean densities had decreased to 2028+/-63 (n=6) and 1568+/-50 (n=6) respectively. In the group of retinas with sham injection, with vehicle alone or with NT-3, RGC densities also decreased by 7 days to 1261+/-71 (n=5), 1506+/-98 (n=10), and 1474+/-125 (n=4), respectively. However, similar densities to those observed in control retinas were observed 7 days after ON transection in the groups of retinas treated with NT-4 (2505+/-91; n=7) or BDNF (2380+/-74; n=7). Fourteen days after axotomy, RGC densities decreased to 521+/-39 (n=10). Comparable densities were found in groups that underwent axotomy and either sham injection (533+/-51; n=5), injection of vehicle (588+/-19; n=10), or NT-3 treatment (634+/-62; n=6). However, at this time, higher densities were observed in the groups treated with NT-4 839+/-39 (n=8) or BDNF 1321+/-120 (n=7). CONCLUSIONS: Axotomy-induced RGC death first appears by day 5 and reaches 80% of the original RGC population by day 12. NT-4 and BDNF administered intraocularly at the time of axotomy exert a neuroprotective effect on axotomy-induced RGC death, thus increasing the population of surviving RGCs and delaying the onset of RGC of axotomy-induced RGC death by approximately 3 days. Intraocular administration of NT-3 did not modify the survival of RGCs after injury.

Animals↗
PubMed1998

Differences in the synaptic complement of thoracic motoneurons of adult and ageing cats after permanent or reversible axotomy.

We have compared the effects of intercostal nerve crush (reversible axotomy) or nerve transection with proximal ligation (permanent axotomy) on the somatic synaptic terminals of thoracic motoneurons of adult (1-2 years) and ageing (10-15 years) cats. Retrograde axonal transport of horseradish peroxidase (HRP) was used to identify axotomised motoneurons; control motoneurons were labelled by the intramuscular injection of HRP. Synaptic frequency and cover of control motoneurons in adult and ageing cats was similar. In adults, 8-16 days following both types of axotomy, synaptic cover was halved without any significant change in synaptic frequency. By 32-64 days following reversible axotomy, synaptic frequency and cover were not significantly different from controls. By contrast, 32-64 days following permanent axotomy synaptic frequency and cover were reduced to 30-50% of adult control values. In ageing cats 2 months following reversible axotomy, synaptic frequency and cover were reduced to 40% and 33% of ageing control values, respectively, while no significant change from controls was found 2 months following permanent axotomy. The long-term synaptic response of axotomised motoneurons in ageing cats is therefore opposite to that of adults.

Age Factors↗
PubMed2000

Androgen receptor mRNA regulation in adult male and female hamster facial motoneurons: effects of axotomy and exogenous androgens.

Testosterone propionate (TP) administration at the time of facial nerve injury in the adult hamster augments the regenerative properties of the injured facial motoneurons (FMN), with the androgen receptor (AR) playing a key role in mediating the actions of TP on facial nerve regeneration. The purpose of the present study was to determine the effects of axotomy on AR mRNA expression in FMN. This was accomplished using in situ hybridization in conjunction with a (35)S-labeled AR riboprobe. Gonadally intact adult male and gonadectomized (gdx) adult female hamsters were subjected to a right facial nerve axotomy, with the left side serving as internal, unoperated control. Half the animals were subcutaneously implanted with a 10-mm TP Silastic capsule, and the other half were sham-implanted. An additional group of nonaxotomized, gonadally intact males was also included. Postaxotomy survival times were 1, 4, and 7 days. At 1 postoperative day 1, there were no effects of axotomy on AR mRNA levels. By postoperative days 4 and 7, axotomy caused a significant decrease in AR mRNA levels in FMN of gonadally intact males, relative to either the contralateral control FMN of the same animals or FMN from the group of gonadally intact males that were not subjected to facial nerve axotomy. There were no significant differences between AR mRNA levels in contralateral control FMN and FMN from the gonadally intact group of nonaxotomized males. TP administration at the time of axotomy had no effect on AR mRNA levels in either the axotomized or contrala(teral control FMN of gonadally intact males, relative to the nonaxotomized, gonadally intact male group. Corroborating our previous work, AR mRNA levels were reduced in the contralateral control FMN of gdx females, relative to the nonaxotomized, gonadally intact male group, with axotomy having no additional effects. The data are discussed in a mechanistic framework suggesting how TP acts to augment facial nerve regeneration.

Animals↗
PubMed2003

Characterization of activated retinal microglia following optic axotomy.

Microglia are prominently involved in neural degenerative diseases of the CNS and the retina. In this study, we determined the activation and phagocytotic function of different subtypes of retinal microglial cells at 1 week and 1 month following optic axotomy. Fluorescent DiI crystals were placed at the stumps of the cut optic nerves of Lewis rats to retrolabel retinal ganglion cells. Microglial cells were indirectly labeled as they phagocytosed the dye particles in the dying ganglion cells. OX-42, 5D4, ED1, and OX-6 antibodies were used for immunohistochemical study. The OX-42- and 5D4-positive microglial cells were increased in the inner retinal layers after optic axotomy. The increase of OX-42-positive cells was considerably greater than that of 5D4-positive cells. The 5D4-positive cells were ramified in shape, whereas OX-42-positive cells were ameboid and ovoid. Both 5D4- and OX-42-positive cells phagocytosed dying ganglion cells at 1 week and 1 month after axotomy. Scattered ameboid ED1-positive cells were detected in the normal retina and showed phagocytotic activity at 1 month after optic axotomy. The number of ED1-positive cells in the retina was unchanged after axotomy. In optic axotomy, three types of microglial cells were activated, namely, 5D4-positive ramified cells and OX-42- and ED1-positive ameboid cells. All of them exhibited the phagocytosis of dying ganglion cells. Insofar as the blood-retinal barrier presumably remained intact in optic axotomy, the OX-42- and 5D4-positive cells might derive from resident microglial cells. The ED1-positive cells, presumably recently blood-borne macrophage in the CNS, remained the same number in the axotomized retina.

Amino Acids↗
PubMed2002

Changes in expression of p38 mitogen-activated protein kinase in the dorsal motor nucleus of the vagus nerve and hypoglossal nucleus after axotomy in adult rats.

Mitogen-activated protein (MAP) kinase cascades are activated in response to various extracellular stimuli. P38 MAP kinase is one of the MAP kinase family and is activated by proinflammatory cytokines and environmental stresses. Activating transcription factor-2 (ATF-2) is one of the targets for p38 MAP kinase. To obtain information on the role of the p38 MAP kinase in the neurons and glial cells after axotomy, we investigated changes of expression of p38 MAP kinase, MAP kinase kinase (MKK) 3, MKK4, MKK6 and ATF-2 in the dorsal motor nucleus of the vagus nerve and the hypoglossal nucleus following axotomy in rats using in situ hybridization and immunohistochemical techniques. Expression of p38 MAP kinase mRNA was observed in the neurons in control rats and showed no remarkable changes after axotomy in both nuclei. On the other hand, expression of p38 MAP kinase mRNA was observed in the perineuronal microglias after axotomy. The expression of p38 MAP kinase, activated p38 MAP kinase, MKK3 and ATF-2 were immunohistochemically observed in neurons of control rats in both nuclei. After axotomy, the expression of p38 MAP kinase, active and inactive, and ATF-2 in neurons were reduced in both nuclei, while expression of mRNA of p38 MAP kinase showed no reduction in neurons. These findings indicate that p38 MAP kinase is functionally regulated not by synthesis but by phosphorylation and regulates the activation of ATF-2 in neurons, and this cascade plays some role in retrograde neuronal reactions. Moreover, perineuronal microglial cells showed strong expression of p38 MAP kinase, active and inactive, after axotomy in both nuclei. These findings suggest that p38 MAP kinase is related to microglial cell reactions after axotomy.

Activating Transcription Factor 2↗
PubMed2003

Corticospinal neurons up-regulate a range of growth-associated genes following intracortical, but not spinal, axotomy.

The failure of some CNS neurons to up-regulate growth-associated genes following axotomy may contribute to their failure to regenerate axons. We have studied gene expression in rat corticospinal neurons following either proximal (intracortical) or distal (spinal) axotomy. Corticospinal neurons were retrogradely labelled with cholera toxin subunit B prior to intracortical lesions or concomitantly with spinal lesions. Alternate sections of forebrain were immunoreacted for cholera toxin subunit B or processed for mRNA in situ hybridization for ATF3, c-jun, GAP-43, CAP-23, SCG10, L1, CHL1 or krox-24, each of which has been associated with axotomy or axon regeneration in other neurons. Seven days after intracortical axotomy, ATF3, c-jun, GAP-43, SCG10, L1 and CHL1, but not CAP-23 or krox-24, were up-regulated by layer V pyramidal neurons, including identified corticospinal neurons. The maximum distance between the lesion and the neuronal cell bodies that up-regulated genes varied between 300 and 500 microm. However, distal axotomy failed to elicit changes in gene expression in corticospinal neurons. No change in expression of any molecule was seen in the neocortex 1 or 7 days after corticospinal axotomy in the cervical spinal cord. The expression of GAP-43, CAP-23, L1, CHL1 and SCG10 was confirmed to be unaltered after this type of injury in identified retrogradely labelled corticospinal neurons. Thus, while corticospinal neuronal cell bodies fail to respond to spinal axotomy, these cells behave like regeneration-competent neurons, up-regulating a wide range of growth-associated molecules if axotomized within the cerebral cortex.

Animals↗
PubMedDate not supplied

[The effects of axotomy on the nociceptive neurons of the leech].

INTRODUCTION: It has been described several similarities between mammalian and invertebrate nociceptors. Lateral N neuron, in the segmental ganglion of the leech Hirudo medicinalis, behave like polimodal nociceptors in mammals, meanwhile medial N cells is similar to mechano nociceptors (Pastor, Soria, Belmonte 1996). The effects of axotomy in sensory neurons in leeches are poorly understood. OBJECTIVE: We have focused on the electrophysiological properties of leech nociceptive neurons after axotomy. RESULTS: In N lateral neurons, axotomy induced an increase in the total membrane capacitance, membrane time constant, decrease in the steady state/maximum hyperpolarization rate, increment in the time constant of voltage relaxation of inward rectifier, increase in action potential duration, dV/dtmax, dV/dtmin, and maximum amplitude and duration of after hyperpolarization; firing threshold (always in not axotomized) and an increment in adaptation spike frequency. In N medial cells, axotomy produced a slight depolarization and a decrease in Rinput, a rise in the time constant of voltage relaxation of inward rectifier, a decrement of action potential maximum amplitude, dV/dtmax, dV/dtmin, and after hyperpolarization maximum amplitude, with an increase in action potential and after hyperpolarization duration. Finally, firing threshold increased both in axotomized and not axotomized after axotomy. Axotomy not only induced changes in injured cells, but modified neurons whose axons did not run into the cutting nerves. CONCLUSION: axotomy induces different changes in N lateral and N medial nociceptive cells, and it is suggested some kind of communication between axotomized and not axotomized cells

Action Potentials↗
PubMed1995

Axotomy induces a different modulation of both low-affinity nerve growth factor receptor and choline acetyltransferase between adult rat spinal and brainstem motoneurons.

Adult rat spinal and brainstem motoneurons re-express low-affinity nerve growth factor receptor (p75) after their axotomy. We have previously reported and quantified the time course of this reexpression in spinal motoneurons following several types of injuries of the sciatic nerve. Other studies reported the reexpression of p75 in axotomized brainstem motoneurons. Results of these previous studies differed regarding the type of the most effective triggering injury for p75 reexpression, the relative duration of this reexpression and the decrease of choline acetyltransferase (ChAT) immunoreactivity (-IR) following a permanent axotomy of spinal or brainstem motoneurons. These differences suggest that these two populations of motoneurons respond to axotomy with a different modulation of p75 and ChAT expression. The aim of the present study was to determine whether differential modulation exists. We have analyzed and quantified the presence of p75- and ChAT-IR motoneurons in the hypoglossal nucleus following the same types of injury and the same time course we previously used for sciatic motoneurons. The results show that a nerve crush is the most effective triggering injury for p75 and that it induces similar temporal patterns of p75 and ChAT expression for sciatic and hypoglossal motoneurons. In contrast, a cut injury of the sciatic and hypoglossal nerves resulted in distinct temporal courses of both p75 and ChAT expression between these two populations of motoneurons. In fact, a permanent axotomy of the hypoglossal motoneurons induced i) a much longer maintenance phase for p75 than in sciatic motoneurons and ii) a progressive loss of ChAT-IR with a successive return to normal values in contrast to the modest decrease in the sciatic motoneurons. This evidence indicates that spinal and brainstem motoneurons respond to a permanent axotomy with a different modulation of p75 and ChAT expression. Altogether, the present data and the reported evidence of a differential post-axotomy cell death support the hypothesis that these two populations of motoneurons undergo different dynamic changes after axotomy.

Animals↗
PubMed1993

Acceleration of axonal outgrowth in rat sciatic nerve at one week after axotomy.

Following injury of sciatic motor axons in the rat, the rate of axonal outgrowth is faster if there has been a prior "conditioning" axotomy. The acceleration of outgrowth is due to an acceleration of SCb, the rate [slow (SC)] component of axonal transport that carries cytomatrix proteins; this occurs throughout the axon by 7 days after the conditioning axotomy (Jacob and McQuarrie, 1991a, J. Neurobiol. 22:570-583). To further characterize the conditioning lesion effect (CLE), it is important to know (1) the minimum effective conditioning interval (time between conditioning and testing lesions), (2) whether the cell body reaction is required, and (3) whether outgrowth accelerates after a single axotomy. Outgrowth distances were measured by radiolabeling all newly synthesized neuronal proteins and detecting those carried to growth cones by fast axonal transport. When the conditioning and testing lesions were made simultaneously (0 day conditioning interval), there was no CLE. With a conditioning interval of 3 days, there was a shortening of the initial delay (before the onset of outgrowth) without a change in outgrowth rate. With conditioning intervals of 7, 14, and 21 days, the rates of outgrowth were increased by 8%, 22%, and 11%, respectively. To determine whether the cell body reaction to axotomy is necessary for the CLE, a nonaxotomizing stimulus to axonal growth (partial denervation) was used in place of a conditioning axotomy. This had no effect on the rate of outgrowth from a testing lesion made 14 days later. Finally, we examined the possibility that outgrowth accelerates after a single lesion. Outgrowth was faster at 6-9 days after axotomy than at 3-6 days (p < 0.001), and accelerated further at 9-12 days (p < 0.001). We conclude that (1) the shortest effective conditioning interval is 3 days; (2) the cell body reaction is necessary for the CLE; (3) axonal outgrowth from a single axotomy accelerates in concert with the anabolic phase of the cell body reaction. The SCb motor is, in turn, upregulated by this reaction. This suggests that the SCb motor responds to a fast-transported signal that is a product of the cell body reaction.

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