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PubMed1995

Number and dendritic morphology of retinal ganglion cells that survived after axotomy in adult cats.

Retinal ganglion cells (RGCs) of adult cats were labeled by injection of diI into the proximal stump of completely transected optic nerves. Approximately 2% to 5% of the RGC population appeared viable 2 months after these axotomies, based on diI retention. The morphological type and dendritic arbor of these surviving RGCs were examined after intracellular injections of Lucifer Yellow into diI-labeled RGCs. Postaxotomy survival rate was much higher for alpha-like cells than for beta-like cells. However, in one of four retinas examined, a large number of RGCs seemed to survive axotomy, and among these, beta cells survived at an unusually high rate. Dendritic arbors of surviving RGCs were also examined after intracellular injection of horseradish peroxidase. Some dendrites of these RGCs lacked branches and were thin in caliber. Other dendrites displayed many spiny processes and bulbous swellings. Essentially, these results confirm the previous suggestion that alpha cells survive axotomy longer than beta cells. The ability of alpha cells to regenerate axons may thus be attributable to their relatively high resistance to axotomy. The atypical dendritic profiles seen after optic nerve transection may reflect either degeneration or regrowth of dendrites.

Animals↗
PubMed1996

Neuropeptide Y expression in the trigeminal ganglion and mandibular division of the trigeminal nerve after inferior alveolar nerve axotomy in young rats.

Neuropeptide Y (NPY) is a 36-amino-acid peptide residing in sympathetic nerve terminals, originating from the superior cervical ganglion in oral tissues. NPY exerts vasoconstrictor action together with noradrenalin and has been found to inhibit the release of neurotransmitters from primary afferent fibers. During regeneration of the axotomized inferior alveolar nerve (IAN), NPY-immunoreactive (IR) nerve fibers have been shown in the odontoblast layer and dentin, an area normally innervated by afferent nerve fibers. The dynamic shift in neuropeptide expression in the trigeminal ganglion and in the dental pulp was studied by immunohistochemistry 1, 2, 3, and 8 weeks after IAN axotomy. In the ipsilateral first mandibular molar a temporal loss of pulpal sensory nerves lasting for approximately 1 week was found after axotomy. An upregulation of NPY was shown in neurons located in the mandibular area of the trigeminal ganglion, concomitant to a reduction in number of neurons expressing substance P (SP). To study an alternate and possible trigeminal origin of some of the peripheral nerve fibers IR to NPY in the dental pulp, double immunofluorescence labeling was performed for NPY and calcitonin gene-related peptide (CGRP). Coexistence of NPY and CGRP was shown in neurons located in the trigeminal ganglion and in nerve fibers in the tooth pulp during IAN regeneration. Furthermore, retrograde tracing with Fluorogold revealed NPY-IR neurons projecting to the first molar pulp 3 weeks after axotomy. Hence, we conclude that after IAN axotomy NPY is produced in trigeminal ganglion neurons and transported in afferent regenerating fibers to the dental pulp. These results add further evidence for a plasticity in peptide transcription in sensory neurons after nerve injury and indicate a trigeminal origin of at least some of the pulpal NPY-IR fibers during nerve regeneration.

Age Factors↗
PubMed1997

Effects of axotomy and testosterone on androgen receptor mRNA expression in hamster facial motoneurons.

We have previously demonstrated that testosterone propionate (TP) treatment accelerates the rate of regeneration following facial nerve crush axotomy in adult male hamsters. These effects are mediated by androgen receptor (AR) activation and are blocked by pretreatment with the AR antagonist, flutamide. In addition to its beneficial effects on regeneration, TP regulates AR mRNA levels in facial motor neurons (FMN). Gonadectomized (gdx) male hamsters have been shown to have approximately 50% of the AR mRNA levels found in gonadally intact males. Administration of TP to gdx males results in an upregulation in AR mRNA levels after 1 day of treatment. Recent reports in the literature suggest that axotomy also may regulate the expression of AR in motor neurons. In this study, we examined the effects of axotomy and exogenous steroid treatment on the regulation of AR mRNA in hamster FMN. Five days after castration, adult male hamsters were subjected to a right facial nerve axotomy. Half the animals received one 10-mm Silastic capsule filled with 100% crystalline TP, and the remainder were sham implanted. Postoperative survival times were 6 h or 1, 2, 4, 7, or 14 days. In situ hybridization in conjunction with an AR riboprobe and computerized image analysis were used to quantify AR mRNA levels. The contralateral FMN served as internal controls for these experiments, and FMN of gonadally intact males served as additional nonaxotomized controls. As predicted, AR mRNA levels were upregulated in contralateral control FMN after TP treatment. However, this TP-induced upregulation of AR mRNA levels did not occur in the axotomized FMN. These results indicate that axonal injury can disrupt the normal regulatory pattern of AR mRNA expression by exogenous steroids in motoneurons. We conclude that the potentiation of regenerative events by TP does not require augmented synthesis of AR, but, instead, enhanced stabilization of existing receptors.

Animals↗
PubMed1996

Influence of leukemia inhibitory factor on galanin/GMAP and neuropeptide Y expression in mouse primary sensory neurons after axotomy.

The effect of unilateral transection of the sciatic nerve on expression of immunoreactive galanin (GAL), galanin-message-associated peptide (GMAP) and neuropeptide tyrosine (NPY) in dorsal root ganglia (DRGs) was studied in wild-type mice and in leukemia inhibitory factor (LIF)-deficient mice. In normal and contralateral DRGs small numbers of weakly fluorescent GAL- and GMAP-positive neuronal cell bodies and numerous positive fibers were observed. No NPY-positive cell bodies but a few fibers surrounding blood vessels were seen. In LIF deficient mice hardly any GAL- or GMAP-positive neurons or fibers were seen, nor was NPY-like immunoreactivity present in cell bodies. After axotomy there was a dramatic upregulation of all three peptides in wild-type DRG neurons, whereby 50-60% of the neuron profiles, encompassing both small and large profiles, were GAL- and GMAP-immunoreactive (IR). About one third of all neuron profiles, mainly large ones, were NPY-positive. In LIF-deficient mice this upregulation was much less pronounced. Thus GAL- and GMAP-IR neuron profiles were reduced by 65-70% compared with the wild-type mice. The number of NPY-positive neuron profiles was reduced to half but this difference was not significant. There was also an ipsilateral decrease in fluorescence intensity for all three peptide immunoreactivities in the LIF-deficient mice as compared with wild-type mice after axotomy. There was no apparent difference in size between, respectively, GAL- and GMAP-positive profiles when comparing LIF-deficient and wild-type mice before or after axotomy. There were, however, no small NPY-IR profiles in the LIF-deficient group. The present results suggests that LIF is important for the dramatic upregulation of GAL and GMAP seen after axotomy. It may also be important for the normal expression of galanin in mouse DRGs, since wild-type mice seemed to have somewhat more positive cell bodies and more fluorescent fibers. LIF seems to be less important for the control of NPY synthesis, but may be involved in NPY regulation in small-sized neurons.

Animals↗
PubMed1979

Ultrastructural data, with special reference to bouton/glial relationships, from the hypoglossal nucleus after a second axotomy of the hypoglossal nerve.

The left hypoglossal nerve of adult male albino rats was prevented from regenerating to the tongue after a distal axotomy by implanting the proximal stump into normally innervated left sternomasoid muscle. Eighty-four days after implantation, the hypoglossal nerve was transected again and its regeneration to the tongue unimpeded. From 8 to 70 days after this second axotomy the left hypoglossal nuclei were processed for quantitative ultrastructural analysis. The first aim of this study was to compare regeneration success in the hypoglossal nucleus after second axotomy with that accompanying outgrowth of the hypoglossal nerve into denervated sternomastoid muscle. During quantitative analysis a second aim developed, of elucidating bouton/glial relationships. The second axotomy induced loss and return of subsurface cisterns, dispersal and reassembly of Nissl substance, increase and decrease of microglial numbers, slight further loss and partial return of boutons with clear spherical vesicles and symmetrical synapses, slight increase and decrease of boutons with clear flat vesicles and symmetrical synapses, regrowth of retracted dendrites and restoration of their synapses, and gradual diminution of numbers of electron-dense neurones and dendrites. Astrocytes remained hypertrophied throughout. When compared with events in the hypoglossal nucleus accompanying innervation of denervated sternomastoid muscle by the hypoglossal nerve, the results suggest (1) that regeneration of the hypoglossal nerve to its own tongue muscle instead of to a foreign muscle caused no acceleration of recovery in the hypoglossal nucleus, and (2) that the microglial response is dependent on nerve integrity and not on bouton behaviour.

Accessory Nerve↗
PubMed1986

Cortically and lingually induced postsynaptic potentials in trigeminal motoneurons after axotomy.

The membrane properties and the efficacy of excitatory and inhibitory synapses were studied in cat masseteric motoneurons (Mass Mns) after axotomy. In axotomized Mass Mns the slope of the primary range in the frequency-current relationship showed a higher gain than that of normal Mass Mns. The safety of antidromic invasion was increased and the initial segment component of antidromic action potentials could not be separated from the soma-dendritic component. In normal Mass Mns a single shock delivered to the orbital gyrus or the lingual nerve induced long-lasting inhibitory postsynaptic potentials (IPSPs). In two-thirds of Mass Mns explored 30 days after axotomy, a single shock delivered to the orbital gyrus or the lingual nerve evoked a mixture of inhibitory and excitatory synaptic potentials. In Mass Mns 50 days after axotomy, we have demonstrated that the major fraction of the total sample of explored Mass Mns showed long-lasting excitatory postsynaptic potentials followed by IPSPs. The results suggest that in Mass Mns, axotomy is followed by the decline of synaptic efficacy of inhibitory rather than of excitatory synapses.

Animals↗
PubMed1977

The effects of postganglionic axotomy and nerve growth factor on the superior cervical ganglia of developing mice.

Sectioning of the two major outflows from the superior cervical ganglia in two week mice results in a marked drop in the number of neurons within one week of operation and a smaller drop over the following two weeks. In animals receiving daily injections of nerve growth factor (NGF), the effect of axotomy is modified. One week after axotomy, the number of neurons in the axotomized ganglia is approximately the same in NGF treated animals as in the control, sham operated ganglia. Over the next two weeks, however, the cell death that results from axotomy is no longer prevented by treatment with NGF. The normal, hyperplastic response to NGF appears to occur independently of the cell reaction caused by axotomy.

Animals↗
PubMed1994

Axotomy induces intranuclear immunolocalization of neuron-specific enolase in facial and hypoglossal neurons of the rat.

Neuron-specific enolase as an enzyme of the glycolytic pathway is localized in the cytoplasm of nerve cells, but not in the cell nucleus. We have applied immunocytochemistry with 1:64,000 polyclonal anti-rat neuron-specific enolase to the brainstem of male and female adult Wistar rats following: (a) transection of the facial nerve with immediate microsurgical nerve suture (facial-facial anastomosis), (b) transection of the hypoglossal nerve with immediate suture (hypoglossal-hypoglossal anastomosis) and (c) transection of the facial and hypoglossal nerve with immediate suture of the proximal hypoglossal to the distal facial nerve stump (hypoglossal-facial anastomosis). Studying the intracellular immunolocalization of neuron-specific enolase in neurons of the facial and hypoglossal nucleus we detected that (1) in normal rats about 20% of all facial and hypoglossal neurons display not only cytoplasmic, but also intranuclear neuron-specific enolase-like immunoreactivity and (2) following any axotomy of the facial or hypoglossal peripheral nerve, the perikarya of all injured motoneurons react by an outstanding increase of neuron-specific enolase-like immunoreactivity in the karyoplasm. Similar findings were obtained in experiments on non-fixed cultured Neuro-2a cells that had been lesioned with hydrogen peroxide. Counting the absolute numbers of normal and reactive neurons at 1-365 days post axotomy revealed that the increase of neuron-specific enolase in neuronal cell nuclei is temporary and reversible. It is first detected at 2 days post axotomy, reaches its maximum at 10-18 days post axotomy and is no longer evident 56 days following surgery.(ABSTRACT TRUNCATED AT 250 WORDS)

Anastomosis, Surgical↗
PubMed1986

Differential effects of axotomy on immature and mature hamster facial neurons: a time course study of initial nucleolar and nuclear changes.

The early nuclear and nucleolar responses at 0.5, 1, 2 and 4 days after axotomy were observed in neurons just before and after the completion of nuclear maturation. Axotomy of hamster facial motor neurons at a postnatal age of 15 days did not produce any changes within the nucleus that were significantly different from those of control cells. In addition, no significant changes were evident in the adults at 0.5 and 1 day after axotomy. At postoperative days 2 and 4, however, the adult neurons showed enlargement of the nucleus and nucleolus. Nucleolonemal strands became more rounded and distinct, and the large cluster of granules located centrally in the nucleolus disaggregated. The irregularly distributed clumps of nucleolus-associated chromatin dispersed to form a thin shell about the nucleolar periphery. In adults at postoperative day 4, the nucleoplasmic granules became more homogeneous and less distinctly outlined than normal. The peak of both nucleolar and nuclear responses coincided at 2 days after injury in the adult, i.e. 2 days before the previously documented chromatolytic peak at 4 days after injury. These studies on the ultrastructural level support our previous hypothesis that the 15-day neurons are synthesizing at peak capacity related to their rapid growth phase and cannot be stimulated further by axotomy. The adult neurons, however, do undergo a metabolic reorganization for regenerative synthesis, and the nucleolar and nuclear changes observed are indicative of transcriptive alterations involving the underlying genome.

Animals↗
PubMed1996

Increased expression of nitric oxide synthase in a subpopulation of rat sympathetic neurons after axotomy - correlation with vasoactive intestinal peptide.

Nitric oxide synthase (NOS) expression is increased in peripheral sensory and central motor neurons after axotomy. By applying double-labelling immunofluorescence and non-radioactive in situ hybridization, we have investigated the regulation of NOS in axotomized sympathetic rat superior cervical ganglia. Furthermore, co-localization of NOS with vasoactive intestinal peptide, which is also induced by axotomy, has been examined. Very few (<0.1%) NOS-expressing neurons are observed in control ganglia. Some large cell bodies located at the exit of the internal carotid nerve are additionally immunoreactive for vasoactive intestinal peptide. One week following postganglionic axotomy, the number of NOS-immunoreactive and NOS mRNA-expressing neurons increases but does not exceed 2% of the whole neuronal population. About 20% of these neurons are also immunoreactive for vasoactive intestinal peptide. Preganglionic nerve fibre meshworks that are immunoreactive for NOS in untreated ganglia disappear after ganglionic decentralization, whereas some presumably postganglionic fibres remain visible after combined axotomy and decentralization. The findings are indicative of an increased synthesis of NOS in a small subset of postganglionic neurons of the rat superior cervical ganglion, possibly because of the loss of target-derived factors that inhibit nitric oxide synthesis under normal conditions.

Adrenergic Fibers↗
PubMed1976

Ultrastructural changes in the developing nucleolus following axotomy.

A large, basophilic, Feulgen-negative structure has been observed within the nucleoli of golden hamster facial motor neurons. This 'intranucleolar body' was seen, at the electron microscopic level, to be composed of granules which are thought to be ribonucleoprotein particles. At 15 days postnatal age, this aggregation of granules had not yet be appeared. However, by 20--24 days, a small intranucleolar body had developed. At maturity, the intranucleolar body had a diameter of up to 2 mum. Facial nerve axotomy at 15 days did not appreciably alter the nucleolar morphology at 19 days; neither control (opposite side) nor experimental nucleoli contained intranucleolar bodies. Normal nucleoli developed intranucleolar bodies, however, between the ages of 20 and 24 days. After axotomy at 20 days and sacrifice at 24 days, a comparison of facial neuronal nucleoli demonstrated that while an intranucleolar body formed in the control, axotomy prevented this structure from forming at its normal time. Also, when the facial nerve of an adult hamster was axotomized and observed 4 days postoperatively, an intact intranucleolar body was not seen. Instead, the granular portions of the nucleolus appeared to have been dispersed into several small aggregates. We believe that the changes observed in granule distribution, both with development and after axotomy, are morphological indications of a qualitative and/or a quantitative change in rRNA synthesis.

Age Factors↗
PubMed1980

Selective synaptic changes following spinal motoneuron axotomy.

Fibers descending in the lateral columns (LC) of the frog spinal cord form synapses more proximal to the soma than those derived from dorsal root (DR) fibers. Following ventral root transection (motoneuron axotomy), the risetime of the LC-EPSP increased while that of the DR-EPSP decreased such that the risetime of the LC-EPSP was now longer than that of the DR-EPSP. Focal-potential analysis showed that the location of LC synapses remained in the region of the motor nucleus while DR synapses were located closer to the motor nucleus after axotomy. Proximal synapses thus persist after axotomy, but they undergo physiological changes that alter the LC-EPSP time course. In addition membrane properties of axotomized motoneurons were investigated. Input resistance, rheobasic current, and threshold depolarization all increased. Resting membrane potentials and afterhyperpolarizations were unchanged. Because axotomy had opposite effects on LC- and DR-EPSPs, changes in membrane properties cannot account for changes in EPSPs. Other possible mechanisms are discussed.

Action Potentials↗
PubMed1988

Loss of transmitter-associated enzyme staining following axotomy does not indicate death of brainstem cholinergic neurons.

To assess the validity of using loss of transmitter-associated enzyme staining to document the death of injured cholinergic neurons, vagal and hypoglossal cholinergic neurons were quantitatively identified at 7 and 28 days following unilateral axotomy using staining procedures for choline acetyltransferase (ChAT) or acetylcholinesterase (AChE), using Nissl stains, and using the retrogradely transported dye, True blue, as an intracellular marker. At 7 days post-axotomy, the transmitter-associated enzymes, ChAT and AChE, had disappeared from over 95% of vagal neurons (P greater than 0.001) and from over 50% of hypoglossal neurons (P greater than 0.001) as compared with the unlesioned control side. At 28 days post-axotomy, ChAT and AChE were still absent from over 70% of vagal neurons (P greater than 0.001) but only from about 15% of hypoglossal neurons as compared with unlesioned control sides. In contrast, no statistically significant losses of either vagal or hypoglossal neurons were found at 7 or 28 days post-axotomy using Nissl stains or detection of retrogradely transported True blue. These findings indicate that transmitter-associated enzyme expression can be regulated independently of neuronal survival following injury. We conclude that absence of transmitter-associated enzyme staining is not an absolute indicator of death of cholinergic neurons.

Acetylcholinesterase↗
PubMed1990

Axotomy-induced temporal dissociation of long-term adaptive changes at neuromuscular synapses of a crayfish phasic motoneuron.

Periodic in situ stimulation of an identified crayfish phasic extensor motoneuron for 3 consecutive days (2 h/day) at 2.5 Hz leads to long-term adaptation (LTA) of its neuromuscular synapses. LTA is characterized by reductions in both initial excitatory postsynaptic potential (EPSP) amplitudes and synaptic depression during repeated stimulation. These adaptive changes were evident 1 day following periodic stimulation. Axotomy of the motoneuron before or after the first day of stimulation of its distal surviving axon abolished both adaptive changes. Axotomy between the second and third stimulation periods abolished only the resistance to synaptic depression. Both adaptive changes were expressed following axotomy after the third day of stimulation. Axotomy alone did not affect neuromuscular transmission in control, unstimulated animals. These results show that axonal continuity between the phasic extensor motoneuron's cell body and its neuromuscular synapses is required at specific times during periodic stimulation for the expression of each of these long-term adaptive changes in neuromuscular transmission. Furthermore, the two adaptive changes in transmission are temporally separable, with the resistance to depression requiring more periodic stimulation to emerge than the reduction in initial EPSP amplitudes. The results also suggest that the molecular components responsible for the expression of these adaptive changes are synthesized in the soma and transported down the axon in response to periodic stimulation of the phasic axon.

Adaptation, Physiological↗
PubMed1992

Evidence that fine primary afferent axons innervate a wider territory in the superficial dorsal horn following peripheral axotomy.

Peripheral axotomy initiates changes in central primary afferent receiving areas of the dorsal horn of the spinal cord. Most of the presently known changes are degenerative in nature and consist of such things as cell and axon death or declines in peptides or enzymes. Other changes are regenerative in nature and because most of these occur in the superficial dorsal horn, which is where fine primary afferents end, we wished to ask whether peripheral axotomy results in a change in the distribution in these fine afferents. Using recently available markers for fine primary afferent axons and small dorsal root ganglion cells, we demonstrate that peripheral axotomy results in a considerable increase in the immunolabeled area for these compounds. Our interpretation is that there may be an extension of fine primary afferent fibers into lamina III and possibly lamina IV following peripheral axotomy. If further work bears out this conclusion, this would provide a possible explanation for the chronic pain states that sometimes follow peripheral nerve damage.

Afferent Pathways↗
PubMed1992

bFGF promotes the survival of entorhinal layer II neurons after perforant path axotomy.

Infusion of basic fibroblast growth factor (bFGF) prevents the loss of cholinergic neurons in the septum/diagonal band of broca following fimbria-fornix transection. However, an in vivo test of whether bFGF will also rescue injured non-cholinergic or cortical neurons has not been carried out. Previous studies have shown that the majority of layer II stellate neurons utilize an excitatory amino acid as their neurotransmitter. In order to determine if bFGF acts on non-cholinergic cortical neurons, a paradigm was developed to examine whether or not bFGF could spare layer II entorhinal stellate cells from axotomy induced death or atrophy. Axotomy of the medial entorhinal cortex fibers projecting to the dentate gyrus of the hippocampal formation via the perforant path lead to retrograde cell loss in entorhinal cortex. Fourteen or thirty days after a unilateral knife cut axotomy of the perforant path, layer II of medical entorhinal cortex showed a 28% decrease in large stellate neurons as well as many weakly stained, hollow cells compared to the non-lesioned side or naive controls. Layer IV neurons, however, which do not project via the perforant path, showed little detectable change in the number of cells ipsilateral to the knife-cut as compared to the contralateral side. Intraventricular infusion of bFGF over a period of 14 days reduced the 28% cell loss to less than 6%. Thus, bFGF is capable of preventing cortical neuronal loss and/or atrophy associated with retrograde degeneration of non-cholinergic neurons following axotomy.

Animals↗
PubMed1993

Flunarizine enhances rat retinal ganglion cell survival after axotomy.

After axotomy most central nervous neurons including retinal ganglion cells (RGCs) die in a few weeks, although their somata are not injured. This neuronal death could be due to lack of retrogradely transported target derived neurotrophic factors or due to a calcium overload after excessive release of excitatory amino acids from dying cells. Flunarizine, as a potent blocker of voltage dependent Ca2+ channels and in higher concentration being an inhibitor of the Ca2+/calmodulin-dependent protein kinase II, is able to mimic the neurotrophic effect of NGF on dorsal root ganglion (DRG) neurons. To examine its neuroprotective value in the central nervous system (CNS), flunarizine (5 mg/kg body weight) was given daily to rats after unilateral axotomy of the optic nerve. The density of retrogradely labelled retinal ganglion cells (RGCs) was determined 14 days after axotomy. It could be demonstrated that flunarizine significantly enhanced RGC survival after axotomy in adult rats (P < 0.001; 1065 +/- 142 vs. 922 +/- 237 RGCs/mm2).

Animals↗
PubMed1993

Axotomy-induced differential gene induction in neurons of the locus ceruleus and substantia nigra.

The biochemical and molecular events correlated with neuronal injury and survival are not well understood. Previous studies have reported that following axotomy, neurons in the substantia nigra pars compacta (SNc) and the locus ceruleus (LC) exhibit a significant increase in tyrosine hydroxylase (TH) enzyme activity within 24-72 h (Brain Res., 144 (1978) 325-342; Brain Res., 92 (1975) 57-72). To investigate the potential contribution of TH gene induction to this increase a semi-quantitative immunocytochemical and in situ hybridization time course analysis was undertaken. Following axotomy, TH immunoreactivity increased in neurons of both the SNc and LC. In contrast, an increase in TH mRNA was only evident in neurons of the LC. As a possible mechanism for the observed alterations in TH gene expression, the levels of an immediate early gene, c-fos, were examined. C-fos mRNA and Fos protein were not expressed in either normal or axotomized neurons of the SNc. However, the constitutive expression in control LC neurons increased significantly following axotomy. These data demonstrate the differential response of two central catecholaminergic populations to axotomy and suggests a potential role for the immediate early gene, c-fos, in the post-injury reaction.

Animals↗