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PubMed1979

Axonal atrophy from permanent peripheral axotomy in adult cat.

The peripheral axons of lower motor and spinal ganglion neurons were permanently transected and not allowed to regrow to target tissue in adult cats by amputation of the hind limb at the hip. The number and sizes of L-7 lower motor neurons at two levels (cell bodies of lateral group motor neurons and myelinated fibers [MFs] of ventral root) and of L-7 spinal ganglion neurons at two levels (cell bodies of L-7 spinal ganglion and MFs of dorsal root) were morphometrically evaluated in groups of cats at 3 months, 9 months, and 18 months after amputation and compared with the number and sizes of neurons in controls or with those on the opposite side. The number of neurons decreased only minimally after amputation. The diameter of neuron cell bodies was only equivocally reduced. By contrast, the median diameter and the peak diameter of both large and small MFs of dorsal and ventral nerve roots were significantly (approximately 30%) less than those of controls. This reduction in diameter of MFs is judged to be related to chronic axonal atrophy rather than to selective loss of large fibers. Permanent transection of distal axons should therefore prove to be a good model of chronic axonal atrophy.

Age Factors↗
PubMed1996

Axotomy-induced retinal ganglion cell death in development: its time-course and its diminution by antioxidants.

Developing neurons die when deprived of trophic support from their axonal target. Although this is generally attributed to the programmed expression of suicide proteins, recent data suggest that a less orderly mechanism involving oxidative stress may also be involved. We have studied retinal ganglion cell death in the chick embryo after a contralateral tectal lesion. The kinetics of cell death, as judged from counts of pyknotic cells, are described. In addition, we show that the pyknotic counts are reduced following intraocular injections of the protein synthesis inhibitor cycloheximide or the antioxidants N-t-butyl-alpha-phenylnitrone and N-acetyl cysteine. Our results suggest that target deprivation-induced ganglion cell death involves oxidative stress.

Acetylcysteine↗
PubMed1993

Regeneration of hypoglossal nerve axons following blockade of the axotomy-induced microglial cell reaction in the rat.

The aim of the present study was to examine whether inhibition of the microglial cell reaction around axotomized motoneurons affects the subsequent regeneration process of the injured axons. The microglial cell reaction in the hypoglossal nucleus of the rat was blocked by infusion of cytosine-arabinoside (ARA-C) into the ventricular system. Axon regeneration was evaluated by determining the number and size distribution of myelinated axons at a defined level distal to the crush site, the number of neurons which could be retrogradely labelled from the distal stump as well as the number of motor endplates in the tongue at various times following injury. No significant difference was observed for any of these parameters between ARA-C-treated and untreated animals. Therefore, it is concluded that the microglial cell reaction is not necessary for peripheral nerves to regenerate and restore target contact at a normal rate and to a normal extent.

Animals↗
PubMed1993

Differential expression of immediate early genes in rubrospinal neurons following axotomy in rat.

Many immediate early genes are rapidly and transiently expressed in the central nervous system following a variety of stimuli. Damage to the axons of peripheral and certain central neurons has been shown to result in a long-term increase in expression of c-Jun in the parent cell bodies. In the peripheral nervous system this increased expression of c-Jun protein and mRNA develops over 24 h following sciatic nerve section and is maintained if the damaged nerve is ligated, but returns to basal levels if the peripheral nerve is allowed to regenerate. Here, we report on the response of rubrospinal neurons to spinal cord hemisection at levels C3 and T10. c-Jun expression was first seen at 12 h post-lesion in a limited number of rubral neurons. The number of positively stained neurons increased up to 10 days post-lesion and then declined over the following weeks. By 7 weeks post-lesion there was still evidence of c-Jun immunoreactivity in both large and other clearly atrophic rubrospinal neurons. c-Fos immunoreactivity was seen only at 12-48 h in a small number of rubrospinal neurons. Evidence from retrograde tracing experiments following fluorogold application to the hemisected cord suggested that all c-Jun-positive neurons projected into the spinal cord. No c-Jun response was seen following a lesion at T10.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1994

Galanin receptor binding sites in adult rat spinal cord respond differentially to neonatal capsaicin, dorsal rhizotomy and peripheral axotomy.

The discrete distribution and possible changes in specific [125I]galanin binding sites were evaluated in the rat spinal cord following neonatal capsaicin treatment, dorsal rhizotomy and sciatic nerve section. The highest density of [125I]galanin binding sites in the normal rat spinal cord was particularly evident in the superficial layers of the dorsal horn whereas moderate to low amounts of labelling were associated with the deeper dorsal horn, areas around the central canal and the ventral horn. Capsaicin-treated rats, compared to littermate controls, showed a significant bilateral increase in [125]galanin binding in the superficial laminae of the dorsal horn. Similarly, unilateral dorsal rhizotomy evoked a significant increase in the density of [125l]galanin binding sites in the superficial dorsal horn ipsilateral to surgery. Section of the sciatic nerve, on the other hand, induced a significant depletion in [125l]galanin binding in laminae I and II of the ipsilateral dorsal horn. These results, in parallel to those reported for galanin immunoreactivity under similar conditions, suggest that [125I]galanin binding sites are preferentially located postsynaptically to the primary afferent fibre terminals in the dorsal horn of the spinal cord. Thus it seems that galanin, at the level of the dorsal spinal cord, regulates the processing of nociceptive information by acting on its own class of specific receptors located postsynaptically to primary sensory terminals.

Animals↗
PubMed1995

Persistence of neuromuscular junctions after axotomy in mice with slow Wallerian degeneration (C57BL/WldS).

The present study was undertaken to examine the fate of neuromuscular junctions in C57BL/WldS mice (formerly known as OLA mice) after nerve injury. When a peripheral nerve is injured, the distal axons normally degenerate within 1-3 days. For motor axons, an early event is deterioration of motor nerve terminals at neuromuscular junctions. Previously, the vulnerability of motor terminals has been attributed either to a 'signal' originating at the site of nerve injury and transported rapidly to the terminals or to their continual requirement for essential maintenance factors synthesized in the motor neuron cell body and supplied to the terminals by fast axonal transport. Mice of the WldS strain have normal axoplasmic transport but show an abnormally slow rate of axon and myelin degeneration. Structure and function are retained in the axons of distal nerve stumps for several days or even weeks after nerve injury in these mice. The results of the present study show that WldS neuromuscular junctions are also preserved and continue to release neurotransmitter and recycle synaptic vesicle membrane for at least 3 days and in some cases up to 2 weeks after nerve injury. Varying the site of the nerve lesion delayed degeneration by approximately 1-2 days per centimetre of distal nerve remaining. These findings suggest that the mechanisms of nerve terminal degeneration after injury are more complex than can be accounted for simply by the failure of motor neuron cell bodies to supply their terminals with essential maintenance factors. Rather, the data support the view that nerve section normally activates cellular components or processes already present, but latent, in motor nerve endings, and that in WldS mice either the trigger or the cellular response is abnormal.

Aging↗
PubMed1996

Leukaemia inhibitory factor induced in the sciatic nerve after axotomy is involved in the induction of galanin in sensory neurons.

Dramatic changes occur in neuropeptide expression in sensory and sympathetic neurons following axonal injury. Based on the finding that the cytokine leukemia inhibitory factor (LIF) plays an important role in mediating these changes in sympathetic neurons, its participation in triggering changes in sensory neurons was examined. By the use of transgenic mice in which the LIF gene had been knocked out, LIF was found to contribute to the induction of galanin expression in dorsal root ganglia (DRG) after sciatic nerve lesion. On the other hand, two other neuropeptide changes that occur in DRG under these conditions, the reduction of substance P and induction of neuropeptide Y, were independent of LIF expression. In the sympathetic superior cervical ganglion, transection of the postganglionic nerves close to the ganglion resulted in a rapid induction of LIF mRNA in the ganglion and in the lesioned nerve trunk. In contrast, transection of the sciatic nerve close to or distant from the DRG caused a rapid induction of LIF mRNA in the lesioned nerve, but not in the DRG. DRG were capable of making substantial amounts of LIF mRNA when placed in explant cultures, but, in vivo, only a slight induction was found even when both central and peripheral nerve processes of these sensory neurons were transected. These latter observations suggest that, in contrast to the superior cervical ganglia, the DRG environment inhibits the lesion-induced expression of LIF in vivo and/or explanted DRG produce stimulatory signals not found in vivo. Together with the data on the induction of galanin, these observations provide evidence that LIF, generated at a site at some distance from the ganglion, is involved in triggering part of the cell body reaction in sensory neurons.

Animals↗
PubMed1996

Chromogranin mRNA levels in the brain as a marker for acute and chronic changes in neuronal activity: effect of treatments including seizures, osmotic stimulation and axotomy in the rat.

Chromogranin/secretogranins are a family of acidic, soluble proteins with a widespread distribution in secretory vesicles of endocrine and nervous tissues. The effects of experimental stimuli of differing duration and intensity on chromogranin B and secretogranin II mRNA levels in relevant areas of the rat brain were examined by in situ hybridization histochemistry using 35S-labelled oligonucleotides. Effects of two 'chronic stimulation' paradigms were studied - the effect of 4 days of water or food deprivation on mRNA levels in the hypothalamus and the effect of unilateral cervical vagotomy on transcript levels in the dorsal vagal complex 1, 2 and 7 days after surgery. After 4 days of water deprivation secretogranin II mRNA was significantly increased in supraoptic nucleus (366 +/- 21% of control, P < 0.01), the magnocellular paraventricular nucleus (209 +/- 20% of control, P < 0.01) and the parvocellular paraventricular nucleus (147 +/- 6% of control, P < 0. 05) after 4 days of food deprivation. Seven days after unilateral cervical vagotomy, secretogranin II and chromogranin B mRNA levels were markedly decreased in the ipsilateral dorsal motor nucleus of the vagus (25 +/- 4 and 47 +/- 8% of contralateral values respectively, P < 0.01). Rapid changes in chromogranin mRNA were also detected following shorter duration 'acute stimulation' - in the hypothalamus after hypertonic saline injection, in the hippocampus after electrical stimulation-induced kindled seizures, and in the cerebral cortex after unilateral craniotomy. A large increase in secretogranin II mRNA was detected in the supraoptic nucleus (202 +/- 25% of control, P < 0.01) and the magnocellular paraventricular nucleus (168 +/- 29% of control, P < 0.05) 3 h after a single intraperitoneal injection of hypertonic (1.8 M) saline. Markedly increased levels of secretogranin II (125-160% of control) and chromogranin B (140-230% of control) mRNA were observed in granule cells of the dentate gyrus 0.5-2 h after amygdaloid stimulation-induced seizures. A moderate increase in secretogranin II mRNA (144 +/- 11% of contralateral side, P < 0.01) was found in the underlying cerebral cortex 2.5 h after unilateral craniotomy. These results indicate that measurement of changes in chromogranin mRNA, particularly secretogranin II, is a useful means of assessing both rapid and long-lasting increases and decreases in neuronal activity and, in contrast to immediate early gene mRNA levels, may better reflect specific changes in neuronal secretory activity associated with transmitter/peptide release.

Animals↗
PubMed2000

Changes in the distribution of synaptic potentials from bulbospinal neurones following axotomy in cat thoracic spinal cord.

1. Plasticity in functional connections of expiratory bulbospinal neurones was investigated by measurement of terminal potentials (TPs) and focal synaptic potentials (FSPs), recorded with spike-triggered averaging in the thoracic spinal cord of anaesthetized, paralysed cats. These measurements were made in normal cats and in those which had previously been subjected to spinal cord lesions that transected the axons of the bulbospinal neurones in the segment below that under investigation, either about 2 weeks or about 16 weeks previously. 2. In both groups of operated animals bulbospinal neurones with firing properties and conduction velocities similar to normal were present. The extracellular recordings that were averaged to reveal TPs and FSPs were made on two standard grids, each consisting of eight sites spaced 0.25 mm apart on two electrode tracks. One grid was positioned at a rostral and one at a caudal location within one segment (T7-T9). 3. Tn the normal animals TPs and FSPs were larger and/or more common at rostral sites than at caudal sites, by a factor of about 1.7. In both 2 week and 16 week animals, TPs and FSPs were observed, both showing normal tine courses and latencies. At rostral sites in 2 week and 16 week animals the amplitudes and/or the frequency of occurrence of TPs and FSPs were similar to normal, as was the case fir caudal sites in the 2 week animals. However, at caudal sites in the 16 week animals the FSPs were mole common and/or significantly larger than normal, with the increase particularly marked on the lateral track, being equivalent to a factor of about 2. A corresponding increase in the amplitude and/or frequency of occurrence of TPs at caudal lateral sites was also seen, but was not significant. 4. The results are interpreted as evidence for short-range sprouting of the bulbospinal axons and the formation by them of new connections in the caudal parts of the segments concerned.

Animals↗
PubMed1985

Uptake and release of gamma-aminobutyric acid in the guinea pig cochlear nucleus after axotomy of cochlear and centrifugal fibers.

This study attempts to determine if gamma-aminobutyric acid (GABA) may be a transmitter of cochlear nerve fibers projecting from the cochlea to the cochlear nucleus, and of centrifugal fibers projecting to the cochlear nucleus via the trapezoid body and the acoustic striae of the medulla. The uptake and the electrically evoked release of exogenous [14C]GABA were measured, in vitro, in the three major subdivisions of the guinea pig cochlear nucleus; the anteroventral, posteroventral, and dorsal cochlear nuclei. These activities were compared using unlesioned animals, animals with bilateral cochlear ablations, and animals whose trapezoid body and acoustic striae were interrupted on the right side of the medulla. Subdivisions from unlesioned animals took up [14C]GABA, achieving concentrations in the tissues that were 11-19 times that in the medium. Electrical stimulation evoked a Ca2+-dependent release of [14C]GABA from each subdivision. Bilateral cochlear ablation, which presumably destroyed the cochlear nerve fibers, had no effect on [14C]GABA uptake and release. Section of the trapezoid body and the acoustic striae on the right side of the medulla typically severed all known connections of the right posteroventral and dorsal cochlear nuclei with the rest of the brain, but left intact many connections involved with the right anteroventral cochlear nucleus. This lesion partially depressed [14C]GABA uptake and release in the right posteroventral and dorsal cochlear nuclei, but not in the right anteroventral cochlear nucleus. These findings suggest that one or more of the centrifugal tracts projecting to the cochlear nucleus may be GABAergic, 88% or more of the cochlear nerve fibers probably are not GABAergic, and some neurons of the cochlear nucleus are probably GABAergic.

Animals↗
PubMed1986

Amino acid levels in the guinea pig spinal gray matter after axotomy of primary sensory and descending tracts.

This study attempts to determine if the axonal endings of dorsal root sensory fibers and of descending axons to the spinal gray matter in the guinea pig store glutamate and/or aspartate. Bilateral dorsal rhizotomy (spinal segments C5-T1) and partial cordotomy (segment C5, right side) were used to interrupt primary sensory and descending tracts, respectively. At 1 and 2 days after surgery, amino acid levels were determined in regions microdissected from areas of the gray matter of spinal segment C7 that receive heavy projections from the primary sensory and the descending tracts. These regions were identified by visualizing the degeneration of axons and their terminal fields in silver-impregnated light microscopic preparations of the spinal cord. After dorsal rhizotomy, the heaviest degeneration in the spinal gray appeared centrally in laminae II-IV and medially in laminae IV-VI. The levels of aspartate, glutamate, and gamma-aminobutyrate were reduced by 34, 21, and 26% in laminae II-IV and 28, 33, and 23% in medial laminae IV-VI. The levels of glycine, alanine, and threonine-serine-glutamine (unseparated) were increased. After partial cordotomy, the heaviest degeneration in the spinal gray appeared laterally in laminae IV-VI, dorsolaterally in lamina VII, and in lamina IX. The levels of aspartate and glutamate were reduced by 22 and 28% in lateral laminae IV-VI and by 26 and 28% in dorsolateral laminae VII and IX. Glycine levels were reduced by 9% in dorsolateral laminae VII and IX. The levels of gamma-aminobutyrate, alanine, and threonine-serine-glutamine were either unchanged or raised. These findings suggest that the axonal endings of the primary sensory and of one or more of the descending tracts probably contain relatively high levels of glutamate and aspartate, and that they may use these amino acids as transmitters. The partial deafferentation of spinal interneurons and the destruction of some propriospinal fibers probably caused the losses of gamma-aminobutyrate and glycine, and contributed modestly to those of aspartate.

Alanine↗
PubMed1988

Uptake and release of glycine in the guinea pig cochlear nucleus after axotomy of afferent or centrifugal fibers.

Glycine may be an inhibitory transmitter in the mammalian cochlear nucleus (CN). This study attempts to determine if cochlear and/or centrifugal projections to the CN use glycine as a transmitter. The high-affinity uptake and electrically evoked release of exogenous [14C]glycine were measured in vitro in the three major subdivisions of the guinea pig CN: the anteroventral, posteroventral, and dorsal cochlear nuclei (AVCN, PVCN, and DCN, respectively). [14C]Glycine (3.4 microM) was taken up by each subdivision, reaching tissue concentrations six to seven times that in the medium. Subsequent electrical stimulation evoked a Ca2+-dependent release of [14C]glycine from each subdivision. These activities were compared in subdivisions fr0m unlesioned animals, and from animals with lesions of centrifugal or cochlear projections to the CN. Two knife-cut lesions were made to interrupt centrifugal projections to the CN lying in the right acoustic striae and trapezoid body. In one group of animals, centrifugal fibers projecting mainly to the right AVCN and PVCN were severed, which reduced [14C]glycine uptake and release by 44-53% in these subdivisions, but not in the right DCN. In another group of animals, fibers projecting mainly to the right PVCN and DCN were severed, which reduced [14C]glycine uptake and release by 33-47% in these subdivisions, but not in the right AVCN. In CN subdivisions contralateral to either lesion there was no significant change in [14C]glycine uptake or release. Neither of these lesions altered the uptake or release of D-[3H]aspartate in the right or the left CN. Ablation of the left cochlea, which presumably destroyed cochlear nerve fibers unilaterally, had no effect on [14C]glycine uptake and release. These observations suggest that centrifugal projections contribute a proportion of the glycinergic synaptic endings in the CN. In addition, some glycinergic endings probably arise from neurons intrinsic to the CN. The cochlear nerve contains very few, if any, glycinergic fibers.

Afferent Pathways↗