Axotomy causes loss of synaptic contacts and loss of muscarinic receptors in the hypoglossal nucleus [proceedings].
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Animals↗
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Fibroblast growth factor-2 protects entorhinal layer II glutamatergic neurons from axotomy-induced death.
The entorhinal cortex is a major relay between the hippocampus and other cortical and subcortical regions. Glutamatergic axons from layer II neurons form the entorhinal cortical projection to the hippocampus via the perforant pathway. We have demonstrated previously that lesion of the perforant pathway causes the death of approximately 30% of entorhinal layer II (ECL2) neurons. To elucidate mechanisms contributing to neuronal death and to investigate strategies preventing it, we identified the phenotype of the vulnerable neuronal population. Sections were immunolabeled with antibodies to the neuronal markers NeuN, glutamate, and calbindin-D28k, and to receptors for fibroblast growth factor-2 (FGFR1) and NMDA (NMDAR1) and were examined using confocal microscopy. Calbindin immunoreactivity was strikingly lamina-specific to ECL2, where one-third of all ECL2 neurons were calbindin-positive. Localization of glutamate revealed that half of the glutamatergic ECL2 neurons coexpressed calbindin. Quantification using unbiased stereology at 9 weeks after lesion of the perforant pathway revealed that the only ECL2 neuronal population that experienced a significant (70%) loss (20% of the total) was the population of glutamatergic ECL2 neurons that did not coexpress calbindin. All ECL2 neurons expressed FGFR1; therefore, we tested the role of FGF-2 in the survival of glutamatergic ECL2 neurons. We grafted fibroblasts genetically engineered to express nerve growth factor or FGF-2 and found that only FGF-2 grafts prevented loss of the vulnerable glutamatergic/calbindin-negative neurons. We present a hypothesis for the selective vulnerability of these glutamatergic/calbindin-negative ECL2 neurons and address the role of FGF-2 in neuronal rescue.
Afferent Pathways↗
Basic fibroblast growth factor has neuroprotective effects on axotomy-induced spinal motoneuron death and wobbler mouse motoneuron disease.
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Animals↗
[Monsynaptic influences from the reticular formation and muscle afferents following axotomy of motor neurons in rats].
Lumbar motoneurons were studied by means of intracellular recording in intact rats and after section of the appropriate ventral roots. In normal motoneurons monosynaptic EPSPs evoked by stimulation of the reticular formation and Ia group muscle afferents showed no difference in amplitude (3.92 +/- 0.17 mV and 3.86 +/- 0.19 mV), but revealed statistically significant difference in time-to-peak (0.71 +/- 0.05 msec and 0.83 +/- 0.06 msec). The membrane potential, the duration and the amplitude of the actionpotentials, and the generation of antidromic actionpotentials showed no difference between normal and axotomized motoneurons. The partial responses were not recorded in axotomized motoneurons. Monosynaptic reticulo-spinal and Ia EPSPs of axotomized motoneurons exhibited longer time-to-peak than those in normal motoneurons. Besides, Ia EPSPs were significantly reduced in amplitude. The changes of monosynaptic reticulo-spinal and Ia EPSPs cannot be explained exclusively by the alterations of the synapses located on the soma and proximal dendrites.
Animals↗
Increased expression of neuronal nitric oxide synthase (NOS) in visceral neurons after nerve injury.
The distribution of nitric oxide synthase immunoreactivity (NOS-IR) and the changes in this distribution after peripheral axotomy were examined in lumbosacral afferent and preganglionic neurons (PGNs) innervating the pelvic viscera of the male rat. The visceral neurons in L6-S1 and L1-L2 dorsal root ganglia (DRG) and in the spinal cord were identified by retrograde axonal transport following injection of Fluorogold (FG) into the major pelvic ganglion (MPG). Axotomy was performed by removing the MPG on one side 2-4 weeks prior to sacrificing the animals. A differential distribution of NOS-IR was detected in DRG cells at different segmental levels of control animals. Significantly greater numbers of NOS-IR cells were present in thoracic (T8, T10, T12; 30-44 cell profiles/section) and rostral lumbar DRGs (L1-L2; 3-15 NOS-IR cell profiles/section) compared to caudal lumbosacral (L5-S1) DRGs (0.2-0.7 cell profiles/section). A significant increase in the number of NOS-IR cells was detected in the L6-S1 DRG (p < or = 0.001; 11 NOS-IR cell profiles/section) but not in the L2 or L5 DRG ipsilateral to axotomy. In these ganglia, an average of 37.0 +/- 4.0% (L6) and 20.6 +/- 2.2% (S1), respectively, of FG-labeled pelvic afferent neurons were NOS-IR compared to 1.1 +/- 0.5% (L6) and 2.5 +/- 1.4% (S1) contralateral to the axotomy. Following axotomy, a significantly greater percentage of dye-labeled pelvic visceral afferents in the L1 and L2 DRG also exhibited NOS-IR in comparison to the contralateral side. Following axotomy, NOS-IR fibers were detected along the lateral edge of the dorsal horn extending from Lissauer's tract to the region of the sacral parasympathetic nucleus (SPN) on the ipsilateral side of the L6 and S1 spinal segments. These NOS-IR fibers were not detected in adjacent spinal segments (L4, L5, or S2). Axotomy also changed the numbers of NADPH-d-positive and NOS-IR cells in the region of the SPN in the L6 spinal segment. Contralateral to the axotomy 38.3 +/- 4.0% of PGNs in the L6 spinal segment were colabeled with NOS-IR; however, ipsilateral to axotomy, a significantly greater percentage (61.0 +/- 3.0%; p < or = 0.01) of PGNs exhibited NOS-IR. Axotomy did not alter the distribution of PGNs in the S1 segment exhibiting NOS-IR. These results indicate that NOS-IR in visceral afferent and PGNs is plastic and can be upregulated by peripheral nerve injury.
Afferent Pathways↗
CD4(+) T cell-mediated facial motoneuron survival after injury: Distribution pattern of cell death and rescue throughout the extent of the facial motor nucleus.
We have previously demonstrated that CD4(+) T cells transiently rescue facial motoneurons (FMN) from axotomy-induced death in immunodeficient mice. Three subpopulations of motoneurons have been observed within the facial motor nucleus following axotomy: one that always survives axotomy (50%), one that is amenable to rescue from axotomy-induced death through the addition of neurotrophic factors or CD4(+) T cells (30-40%), and one that always dies after axotomy (10-15%). The objective of this study was to anatomically map the extent of axotomy-induced cell death and immune cell rescue in the facial nucleus to study the differential survival capabilities of each subpopulation. Wild-type (WT) mice, recombinase activating gene 2 knockout (RAG-2 KO) mice, and RAG-2 KO mice reconstituted with CD4(+) T cells were subjected to right facial nerve axotomy. At 4 weeks post-axotomy, topographical mapping of axotomy-induced cell death throughout the rostro-caudal extent of the facial nucleus was accomplished in accordance with previously published maps of the subnuclear arrangement of the facial neurons. The results indicate that all 3 subpopulations of FMN can be found in each of the subnuclear groups throughout the entire rostro-caudal extent of the facial nucleus. These data are discussed in context of recent work in amyotrophic lateral sclerosis, a fatal motoneuron disease.
Animals↗
Neurotrophic agents prevent motoneuron death following sciatic nerve section in the neonatal mouse.
We have examined the ability of different neurotrophic and growth factors to prevent axotomy-induced motoneuron cell death in the developing mouse spinal cord. After postnatal unilateral section of the mouse sciatic nerve, most motoneuron (MN) loss occurs in the lateral motor column of the fourth lumbar segment (L4). Significant axotomy-induced cell death occurred after surgery performed on or before postnatal day (PN) 5. In contrast, no significant cell loss was found when axotomy was performed after PN10. Axotomy on PN2 or PN5 resulted in a 44% loss of L4 motoneurons by 7 days, and a 66% loss of motoneurons by 10 days postsurgery. Implantation of gelfoam presoaked in various neurotrophic factors at the lesion site rescued axotomized motoneurons. Nerve growth factor (NGF), neurotrophin-4/5 (NT-4/5) and ciliary neurotrophic factor (CNTF) rescued 20%-30% of motoneurons, whereas brain-derived neurotrophic factor (BDNF), neurotrophin-3 (NT-3), and insulin-like growth factor 1 (IGF-1) rescued virtually all motoneurons from axotomy-induced death. By contrast, platelet-derived growth factor (PDGF)-AA, PDGF-AB, basic fibroblast growth factor (bFGF), and interleukin (IL-6) were ineffective on motoneuron survival following axotomy. NGF, BDNF, NT-3, IGF-1, and CNTF also prevented axotomy-induced atrophy of surviving motoneurons. These data show that mouse lumbar motoneurons continue to be vulnerable to axotomy up to about 1 week after birth and that a number of trophic agents, including the neurotrophins, CNTF, and IGF-1, can prevent the death of these neurons following axotomy.(ABSTRACT TRUNCATED AT 250 WORDS)
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The immunophilin ligand FK506, but not GPI-1046, protects against neuronal death and inhibits c-Jun expression in the substantia nigra pars compacta following transection of the rat medial forebrain bundle.
The immunophilin ligand FK506 (Tacrolimus) is used for prevention of graft rejection following organ transplantation. FK506 is a high-affinity ligand for FK506-binding proteins, an immunophilin subgroup of peptidyl-prolyl-cis/trans-rotamases abundant in the mammalian brain. Here, we demonstrate that FK506 is a potent survival factor that prevents neuronal cell death following axotomy of central intrinsic neurons. Administration of FK506 (2 mg/kg, s.c., per day for two days pre-axotomy and for up to eight days post-axotomy) effectively delayed and reduced the death of axotomized neurons in the substantia nigra pars compacta following transection of the medial forebrain bundle. In saline-treated controls, 75%, 89% and 92% of nigral neurons died after 25, 50 and 60 days post-axotomy, respectively. In contrast, application of FK506 resulted in survival of 46%, 44% and 28% of the axotomized nigral neurons, and the majority of these surviving neurons showed continuous expression of tyrosine hydroxylase, the pacemaker enzyme for dopamine synthesis. Moreover, FK506 significantly reduced the expression of the inducible transcription factor c-Jun and its N-terminal phosphorylation and prevented the axotomy-induced suppression of the constitutive transcription factor ATF-2 in neurons of the substantia nigra and mammillary body. The latter is also axotomized by the coincident transection of the mammillothalamic tract, but the mammillary neurons survive the axotomy. In contradistinction to FK506, the non-immunosuppressive FK506-binding protein ligand GPI-1046 (25 or 12.5 mg/kg, applied once or twice per day for two days pre-axotomy and for eight days post-axotomy) was completely ineffective for all these parameters investigated. Finally, FK506, but not GPI-1046, impressively accelerated the recovery from surgery. Our data provide the first evidence that FK506 acts as a neuroprotective molecule that rescues axotomized otherwise degenerating central intrinsic neurons in the adult mammalian brain by mechanisms that interfere with the transcriptional program of the axotomy-induced cell body response, such as activating transcription factor-2 suppression and c-Jun expression and phosphorylation.
Animals↗
Transection of the rat olfactory nerve increases glial fibrillary acidic protein immunoreactivity from the olfactory bulb to the piriform cortex.
Astrocytic glial fibrillary acidic protein (GFAP) immunoreactivity in response to retrograde changes of motoneurons after axotomy has been the subject of a number of reports. In contrast, this study examined the astrocytic GFAP immunoreactivity in response to axotomy in a sensory system, the adult rat olfactory system. The purpose of this study was to determine, by immunolabeling GFAP, the extent and transience of astrocytic reactivity in the olfactory system. Unilateral transection of the olfactory nerve fascicles was performed intracranially at the level of the cribriform plate. Rats were allowed to survive from 24 hours to 1 month after axotomy. GFAP immunolabeling was examined throughout the rat olfactory system using the peroxidase-anti-peroxidase method. After axotomy, a transient increase occurred in the astrocytic GFAP immunoreactivity in the ipsilateral olfactory system. The greatest enhancement of GFAP immunoreactivity in the olfactory system occurred at 48 hours post-axotomy. Increased GFAP immunoreactivity occurred not only along the axons and synaptic endings of the injured primary olfactory neurons, but also along the dendrites, cell bodies, axons, and synaptic endings of the secondary sensory neurons. The increased GFAP immunoreactivity was specifically associated with the anatomical distribution pathways of the primary and secondary olfactory neurons. Increased GFAP immunoreactivity was not altered until 14 days post-axotomy. At 1 month post-axotomy, GFAP immunoreactivity returned to control levels. The time course and transience of increased GFAP immunoreactivity closely correlates with the time course of rat primary olfactory neuronal degeneration and regeneration after axotomy.(ABSTRACT TRUNCATED AT 250 WORDS)
Animals↗
Upregulation of NMDARI mRNA induced by MK-801 is associated with massive death of axotomized motor neurones in adult rats.
Studies on the pathogenesis of human motor neurone disease have suffered from the absence of models of motor neurone degeneration in adult animals. Normally in adult rodents, transection of motor neurone axons results in only a modest degree of neuronal death. We reasoned that axotomy-induced motor neurone death might be enhanced by modulating glutamatergic transmission. By axotomizing the facial nerve in adult rats and then administering MK-801 for the first week of a 4-week or 8-week post-lesion survival period, we induced a 67% motor neurone loss by 8 weeks as compared with a 19% loss in controls. A possible explanation for the increased motor neurone loss after MK-801 treatment is that transient blockade of NMDA receptors may upregulate synthesis of NMDA receptor components. In order to test this idea, we employed quantitative in situ hybridization to determine the response of NMDAR1 mRNA to axotomy and axotomy + MK-801 treatment. Quantification of the percentage of area occupied by NMDAR1 silver grains per motor neurone somata indicated that axotomy alone did not provoke a change in NMDAR1 mRNA. However, axotomy and MK-801 combined treatment resulted in a highly significant upregulation of NMDAR1 mRNA when compared with controls or animals treated solely with axotomy. Our results suggest that motor neurone death in adult animals can be enhanced after axotomy in association with the upregulation of NMDA receptor mRNA. Thus, abnormalities in glutamate receptor signalling may lead to subacute motor neurone death in vivo. Furthermore these results indicate that transient treatment with MK-801 is a convenient method for enhancing the degree of motor neurone death after axotomy in adult animals.
Animals↗
Changes in brain-derived neurotrophic factor and trkB receptor in the adult Rana pipiens retina and optic tectum after optic nerve injury.
In this study we used immunocytochemistry to investigate the distribution of brain-derived neurotrophic factor (BDNF) and its receptor tyrosine kinase (trkB) in retina and optic tectum of the frog Rana pipiens during regeneration after axotomy. We also measured changes in BDNF mRNA in retina and tectum. Retrograde labeling was used to identify retinal ganglion cells (RGCs) prior to quantification of the BDNF immunoreactivity. In control animals, BDNF was found in the majority of RGCs and displaced amacrine cells and in some cells in the inner nuclear layer (INL). After axotomy, BDNF immunoreactivity was reduced in RGCs but increased in the INL. BDNF mRNA levels in the retina remained high before and after axotomy. Three months after axotomy, after reconnection to the target, the staining intensity of many of the surviving RGCs had partially recovered. In the control tectum, BDNF staining was present in ependymoglial cells and in neurons throughout layers 4, 6, 8, and 9. After axotomy, BDNF staining in tectal neurons became more intense, even though mRNA synthesis was transiently down-regulated. In control retinas, trkB receptor immunostaining was present in most RGCs; no significant changes were observed after axotomy. In control tectum, trkB was detected only in ependymoglial cells. After axotomy, many neuronal cell bodies were transiently labeled. Our data are consistent with the hypothesis that a considerable fraction of the BDNF normally present in RGCs is acquired from their targets in the tectum. However, there are also intraretinal sources of BDNF that could contribute to the survival of RGCs.
Animals↗
The proximity of the lesion to cell bodies determines the free radical risk induced in rat rubrospinal neurons subjected to axonal injury.
To find out whether close axonal injury resulted in greater free radical risk to cord-projection central neurons than distant ones, we studied the expressions of nitric oxide synthase, calcineurin, and superoxide dismutase in rat rubrospinal neurons following brainstem, C2 and T10 axotomies using immunohistochemical methods. We found that nitric oxide synthase expression was upregulated more following brainstem than C2 lesion while T10 lesion triggered no detectable changes. This response peaked at 1 week and returned to control level by 8-week-post-injury. At the same time, calcineurin, which activated nitric oxide synthase, was increased 1 week following brainstem and C2 axotomies. These suggest that close, but not distant, axotomy enhanced NO production, which appeared to be cytotoxic since blocking NO synthesis with N-nitro- l-arginine methyl ester reduced brainstem axotomy-induced rubrospinal cell loss. On the other hand, the mitochondrial Mn-superoxide dismutase, which competes with NO to prevent the formation of the cytotoxic free radical peroxynitrite, was notably reduced after brainstem but almost unaltered following C2 axotomy. Meanwhile, the cytosolic Cu/Zn-superoxide dismutase was not altered following C2 but increased after brainstem axotomy. Ultrastructurally, in rubrospinal neurons more mitochondria became swollen following brainstem than C2 axotomy. Based on these, we proposed that besides the NO-overproduction-induced toxicity, superoxide-loading-induced mitochondrial damage also added to hampering the survival of the closely axotomized neurons.
Animals↗
BDNF regulation of androgen receptor expression in axotomized SNB motoneurons of adult male rats.
Brain-derived neurotrophic factor (BDNF) prevents the axotomy-induced loss of androgen receptor-like immunoreactivity (AR-LI) in the spinal nucleus of the bulbocavernosus (SNB) motoneurons of adult male rats. In this report, we investigated the dose-response effect of BDNF on androgen receptor expression in axotomized SNB motoneurons, and examined whether delayed application of BDNF to the cut SNB axons can completely reverse the axotomy-induced loss of androgen receptor expression. We also used autoradiography to test whether axotomy decreases the ability of SNB motoneurons to accumulate androgens. SNB motoneurons were axotomized bilaterally and BDNF or PBS was applied to the proximal ends of the axons. The percentage of SNB motoneurons expressing medium or high AR-LI was the major measure of androgen receptor expression. AR-LI was significantly higher on the BDNF-treated side than on the contralateral side treated with phosphate-buffered saline (PBS) for all three doses of BDNF (1.45, 2.9, and 5.8 mg/ml) and was higher than in rats treated bilaterally with PBS. Moreover, AR-LI at the highest dose of BDNF was not different from that in intact SNB motoneurons. Delayed application of BDNF to the axotomized SNB motoneurons restored the AR-LI to the intact level. The AR-LI decreased by axotomy started to increase significantly 4 days after BDNF application and returned to the intact level by 10 days. Furthermore, axotomy significantly decreased the percentage of SNB motoneurons to accumulate tritiated testosterone or its metabolites. In conclusion, our data demonstrate that BDNF completely prevents and reverses the axotomy-induced loss of AR-LI. Moreover, decrease of AR-LI by axotomy reflects the decrease in the ability of SNB motoneurons to accumulate androgens.
Animals↗
Restoration of external urethral sphincter function after pudendal nerve end-to-end anastomosis in the male rabbit.
PURPOSE: In this study we rehabilitated external urethral sphincter function by pudendal nerve end-to-end anastomosis after experimental pudendal nerve axotomy in male rabbits. MATERIALS AND METHODS: A total of 17 animals were included in this study, including group 1-a control group of 5 (29.4%), group 2-6 (35.3%) and group 3-6 (35.3%). Animals from group 2 underwent bilateral axotomy and group 3 underwent pudendal nerve end-to-end anastomosis. In all groups we performed urodynamic investigations prior to axotomy, after axotomy or anastomosis, and 14, 42 and 90 days after axotomy or nerve anastomosis. RESULTS: In untreated group 1 control sphincter pressure was 28.5 cm H2O. In group 2 average urethral sphincter pressure was 5.6 cm H2O 14 days after axotomy with only a slight increase to 11.05 cm H2O by day 90. In group 3 external urethral pressure increased to 8.26 cm H2O after 14 days and to 21.32 cm H2O by postoperative day 90. CONCLUSIONS: External urethral sphincter deficiency after bilateral pudendal nerve axotomy demonstrates the primacy of the pudendal nerve in the innervation of the external urethral sphincter. We were able to rehabilitate external urethral sphincter function by performing pudendal nerve end-to-end anastomosis.
Anastomosis, Surgical↗
Age-dependent synapse withdrawal at axotomised neuromuscular junctions in Wld(s) mutant and Ube4b/Nmnat transgenic mice.
Axons in Wld(S) mutant mice are protected from Wallerian degeneration by overexpression of a chimeric Ube4b/Nmnat (Wld) gene. Expression of Wld protein was independent of age in these mice. However we identified two distinct neuromuscular synaptic responses to axotomy. In young adult Wld(s) mice, axotomy induced progressive, asynchronous synapse withdrawal from motor endplates, strongly resembling neonatal synapse elimination. Thus, five days after axotomy, 50-90 % of endplates were still partially or fully occupied and expressed endplate potentials (EPPs). By 10 days, fewer than 20 % of endplates still showed evidence of synaptic activity. Recordings from partially occupied junctions indicated a progressive decrease in quantal content in inverse proportion to endplate occupancy. In Wld(s) mice aged > 7 months, axons were still protected from axotomy but synapses degenerated rapidly, in wild-type fashion: within three days less than 5 % of endplates contained vestiges of nerve terminals. The axotomy-induced synaptic withdrawal phenotype decayed with a time constant of approximately 30 days. Regenerated synapses in mature Wld(s) mice recapitulated the juvenile phenotype. Within 4-6 days of axotomy 30-50 % of regenerated nerve terminals still occupied motor endplates. Age-dependent synapse withdrawal was also seen in transgenic mice expressing the Wld gene. Co-expression of Wld protein and cyan fluorescent protein (CFP) in axons and neuromuscular synapses did not interfere with the protection from axotomy conferred by the Wld gene. Thus, Wld expression unmasks age-dependent, compartmentally organised programmes of synapse withdrawal and degeneration.
Aging↗
Noxa is a critical mediator of p53-dependent motor neuron death after nerve injury in adult mouse.
Axotomy-induced motor neuron death occurs within a week in the neonatal rat and mouse. However, slowly progressive motor neuron death, which takes more than a month, occurs after axotomy in the adult mouse (C57BL/6) but not in the adult rat (Wistar). Here we demonstrate that expression of a p53-inducible Bcl-2 homology domain 3 (BH3)-only protein, Noxa, is enhanced in axotomized neurons of the adult mouse but not in the adult rat. In p53-deficient mice, slowly progressive neuronal death was suppressed and accompanied by reduced Noxa expression after axotomy. However, a minor response of Noxa expression was still observed after axotomy in p53-deficient mice, suggesting that p53-independent Noxa expression occurs to a minor extent. Noxa-deficient mice were used to confirm the consequence of Noxa expression in nerve-injured mouse motor neurons. In Noxa-deficient mice, axotomy-induced motor neuron death was suppressed. Furthermore, among the BH3-only protein members examined, Noxa exhibited the most marked upregulation after axotomy in the mouse. In conclusion, motor neuron death seen in the adult mouse is mainly p53 dependent, and Noxa is a major executor for axotomy-induced motor neuron death in the adult mouse, as a mediator located downstream of p53.
Animals↗
Removal of dorsal root afferents prevents retrograde death of axotomized Clarke's nucleus neurons in the cat.
We investigated the effect of axotomy, deafferentation, and deafferentation plus axotomy on cell survival and cell size in Clarke's nucleus of the cat spinal cord. Hemisection of the adult spinal cord at T9 leads to retrograde cell death of 40% of the neurons in Clarke's nucleus at L3, as well as to a reduction in the mean soma size of the survivors. In contrast, deafferentation of Clarke's nucleus neurons by L1-S2 dorsal rhizotomy produces no cell loss and no shrinkage of the somata. These results indicate that dorsal root afferent input is not required for Clarke's nucleus cell survival. To test whether afferents may be required by the 60% of neurons that survive axotomy, we deafferented Clarke's nucleus prior to axotomy. Surprisingly, removal of primary afferents to Clarke's nucleus neurons prior to axotomy prevented the death of all neurons that would normally have died from axotomy. These results suggest that dorsal root afferent input is not required for Clarke's nucleus neuron survival after axotomy and may in fact be toxic to these axotomized neurons. This afferent toxicity is likely to be mediated through the dorsal root afferent neurotransmitter glutamate.
Afferent Pathways↗
Immediate early gene expression in axotomized and regenerating retinal ganglion cells of the adult rat.
To determine if axotomy-induced immediate early gene (IEG) expression accompanies regenerative efforts in central nervous system (CNS) neurons, immunohistochemistry using antibodies to c-Jun, JunD, JunB, c-Fos, FosB and Krox-24 proteins was used to examine gene expression in identified adult rat retinal ganglion cells (RGCs) under two conditions: (1) after axotomy alone, and (2) 1 month after replacement of the optic nerve with an autologous peripheral nerve graft to allow axonal regrowth. Strong RGC c-Jun expression was induced 1 day, but not 3 h, after axotomy in most RGCs and was maintained in surviving cells throughout the 3-week study period. Axotomy also induced a limited number of RGCs to express Krox-24, but only transiently. c-Fos expression was also seen in a limited number of control RGCs, however, it was not induced by axotomy. Nucleolar FosB immunoreactivity in axotomized RGCs persisted 1 day after axotomy, but was subsequently lost. One month after axotomy and peripheral nerve graft placement, identified RGCs with regrown axons showed only nuclear c-Jun and nucleolar FosB expression. These findings support a role for IEG expression in the regeneration process of CNS neurons.
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