[The dentition and its innervation--a continuously changing system].
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Aging↗
Biomedical subjects
C Hildebrand
Publications and source records attributed to C Hildebrand.
Fibre composition of the feline trochlear and abducens nerves.
Cat trochlear and abducens nerves were studied by electron microscopy at two different levels. Five mm peripheral to the exit from the brainstem, the average number of myelinated axons is 965 in the trochlear nerve and 1901 in the abducens nerve. The size spectrum is unimodal and small myelinated axons predominate. Both nerves contain 16% unmyelinated axons at this level. At the PNS/CNS transition, the nerve fascicles contain few unmyelinated axons, but bundles of such axons are present in the adjacent pia mater. We suggest that the trochlear and abducens nerves may channel unmyelinated sensory and/or autonomic axons to the leptomeningeal blood vessels and the pia mater of the brainstem.
Abducens Nerve↗
Trigeminal alveolar nerve of the lower jaw in the cichlid Tilapia mariae: evidence for continual axon generation and presence of exceptionally small myelinated axons.
Cross sections from the trigeminal alveolar nerve of the lower jaw in the cichlid Tilapia mariae were examined by electron microscopy. The nerve fibers are arranged in groups with a core of unmyelinated and small myelinated axons, surrounded by myelinated axons of varying sizes. The core contains large bundles of unmyelinated axons collectively ensheathed by circumferentially located Schwann cells, as well as smaller bundles of unmyelinated axons partly separated from each other by Schwann cell processes. Among the unmyelinated axons, occasional scattered profiles resembling growth cones are seen. The total number of axons in this tooth-related nerve increases from approximately 1,500 to 5,000, as the animals grow in length from 4.5 to 21.5 cm. Some 24-49% of the axons are unmyelinated. The myelinated axons have maximum diameters of 1.0-3.0 micron, depending on body size. Most myelinated axons have diameters less than 1.0 micron and the smallest ones reach down to 0.3 micron. These results show that there is a continual addition of axons to the alveolar nerve of the lower jaw in Tilapia mariae and that the critical diameter for myelination in this peripheral nerve is similar to that typically found in the mammalian CNS.
Animals↗
N2-phenyldeoxyguanosine: a novel selective inhibitor of herpes simplex thymidine kinase.
A series of N2-substituted guanine derivatives was screened against mammalian thymidine kinase and the thymidine kinase encoded by type I herpes simplex virus to examine their capacity to selectivity inhibit the viral enzyme. Several bases, nucleosides, and nucleotides displayed selective activity. The mechanism of action of the most potent derivative, N2-phenyl-2'-deoxyguanosine (PhdG) was studied in detail. PhdG (a) inhibited the viral enzyme competitively with respect to the substrates thymidine and deoxycytidine, (b) was completely resistant to phosphorylation, (c) displayed limited toxicity for the HeLa cell lines employed as hosts for viral infection, and (d) selectively inhibited viral thymidine kinase function in intact cultured cells. The results indicate that the PhdG drug prototype has potential as a selective anti-herpes agent and as a novel molecular probe of the structure and function of herpes simplex thymidine kinase.
Antiviral Agents↗
Nodes of Ranvier in acrylamide neuropathy: voltage clamp and electron microscopic analysis of rat sciatic nerve fibres at proximal levels.
Adult male rats were injected with acrylamide monomer (50 mg/kg i.p., 3 times/week). The animals developed hind limb paresis and distal motor nerve conduction velocity decreased. Three of 14 examined isolated myelinated sciatic nerve fibres showed a reduced excitability. In the remaining fibres the action potentials were normal. Potential clamp analysis of nodes of Ranvier in the single fibres revealed large delayed nodal K currents in 6 cases. Four of these 6 fibres exhibited a markedly increased membrane capacitance and in 2 fibres an increased Na permeability was found. Electron microscopic examination of sciatic nerves revealed comparatively subtle internodal and nodal-paranodal alterations in large myelinated fibres. Internodally, focal aggregates of tubulovesicular profiles could be found and some Schwann cells were hypertrophic. Paranodally, axonal evaginations penetrated in between the terminating myelin lamellae. Some paranodes had a very thin myelin covering and/or exhibited varying degrees of myelin sheath retraction. In the nodal axon domains lacking an axolemmal undercoating and partly non-undercoated axolemmal protrusions could be found. Similar physiological and morphological alterations occur in the rat sciatic nerve above a neuroma. Therefore, the presently observed proximal changes may, to some extent, represent non-specific alterations, secondary to a target deprivation caused by the distal axon degeneration typical for acrylamide neuropathy.
Acrylamide↗
Voltage-clamp analysis of nodes of Ranvier in regenerated rat sciatic nerve.
Crush-lesioned adult rat sciatic nerves were allowed to regenerate during 70-181 days. Single large regenerated nerve fibres were isolated from levels distal to the crush site, and mounted in a feedback system for potential recordings and voltage clamp. After the experiment, each isolated fibre was fixed and embedded for morphological evaluation. Internodal lengths and fibre diameters were obtained form teased preparations of regenerated and normal sciatic nerves. The isolated regenerated fibres were excitable and had action potentials of large amplitude. TEA and 4-AP had negligible effects on the action potential and excitability properties. The time constant of the nodal segment was larger than in normal fibres. The nodal Na and K permeabilities (PNa and PK) were calculated both in absolute values and relative to the leak conductance (gL). Regenerated fibres had normal PNa/gL and PK/gL ratios. The potential dependence of PNa activation and inactivation was also normal. The isolated physiologically examined fibres had internodal lengths (L) of about 300 micron and diameters (D) of about 7-11 micron. In the teased fibre preparations L was about 300 micron (range 150-600 micron) and D was 3-11 micron. In addition, all teased regenerated nerve preparations exhibited a few scattered unusually short internodes (L less than 150 micron). In control nerves L ranged from 150 micron in the lower fibre size range (D = 2-3 micron) to 1.6 mm in the upper size range (D = 15 micron).
Action Potentials↗
Nodal spacing along regenerated axons following a crush lesion of the developing rat sciatic nerve.
The relation between internodal length (L) and fibre diameter (D) was examined light microscopically in teased specimens from normal developing rat sciatic nerves, and from rat sciatic nerves which had regenerated following crush lesions at various postnatal ages. In newborn rat pups virtually all sciatic nerve axons are unmyelinated and myelination is an essentially postnatal event. Between 2 weeks and 6 months maximal L increases from 500 microns to 1400 microns and maximal D increases from 6-8 microns to 16 microns. The increase in L matches the length growth of the hindlimb. Signs of myelin sheath remodelling are absent during normal development. Examination of regenerated nerves showed that the lengths of the internodes along large-medium-sized axons, are strongly dependent on crush age. In neonatally crushed nerves, the slope is close to normal. With increasing crush age the inclination of the regression line gradually decreases. Signs of myelin sheath remodelling are not seen in regenerated nerves crushed at birth or 1-2 weeks after birth. However, such signs are present in regenerated nerves crushed 3 weeks or more after birth. These observations support the view that myelin sheath remodelling in regenerated rat sciatic nerves is directly related to a deficient length growth following myelination.
Age Factors↗
Nerve growth to tooth buds after homotopic or heterotopic autotransplantation.
Feline permanent incisor tooth buds (bell stage) were autotransplanted to mandibular alveolar sockets (homotopic site) or to the submandibular subcutis or the leg (heterotopic sites). This was done in 34 kittens aged 1-2 months. After survival times of 3-8 months the animals were fixed by glutaraldehyde perfusion. A total of 56 mineralized teeth, which had developed at the recipient sites, were removed, demineralized and processed for light microscopic (LM) general evaluation. Fourty-four teeth, which were judged to be grossly normal in the LM, were selected for electron microscopic (EM) analysis with respect to the occurrence of pulpal nerve fibres. The highest proportion of normal teeth (16 of 16) was obtained from the alveolar site, followed by the submandibular (11 of 14) and hindlimb (17 of 26) sites. Most of the grossly normal grafts possessed pulpal axons (37 of 44). The alveolar grafts were all innervated and exhibited a largely normal appearance qualitatively and in terms of percentage of myelinated fibres. The proportion of innervated pulps was lower among the heterotopic mandibular (10 of 11) and hindlimb (11 of 17) grafts. In addition, signs of nerve fibre degeneration appeared more frequently at the heterotopic sites. On the basis of these findings, and in view of the results of other workers, we conclude that tooth germs are attractive targets for all divisions of the trigeminal nerve and for cutaneous nerves outside the trigeminal system. However, the morphological picture tends to become increasingly abnormal with increasing distance from the normal locus.
Alveolar Process↗
Physiological properties of regenerated rat sciatic nerve following lesions at different postnatal ages.
Electrophysiological properties of regenerated sciatic nerves were examined in vitro following sciatic crush lesions performed on rats at 1 week to 4 months of age. Pharmacological blockade of potassium channels with 4-aminopyridine (4-AP) in control nerves resulted in only minimal changes in the waveform of whole nerve responses, but was associated with slight prolongation of relative refractory periods and compromised frequency-following abilities at all ages examined. A more marked sensitivity to application of 4-AP was observed in all regenerated nerves compared to control nerves. This sensitivity was characterized by the development of a prominent delayed negativity of the compound action potential. Specific features of the waveform alterations differed for nerves crushed before age 3 weeks compared to those injured at the older postnatal ages. Alteration of refractory properties and frequency-following abilities of regenerated nerves following 4-AP were also more pronounced than in control nerves with the most marked disruption being observed in nerves from animals lesioned at the older ages. These data suggest that the process of regeneration is modified by ongoing maturation at the time of crush.
4-Aminopyridine↗
Nodes of Ranvier above a neuroma in the rat sciatic nerve: voltage clamp analysis and electron microscopy.
Neuroma formation was induced in adult rat sciatic nerves and the animals were allowed to survive for 1-10 months. In 10 animals single large myelinated fibres from the nerve segment above the neuroma were subjected to voltage clamp analysis. Six animals were fixed by glutaraldehyde perfusion and nodes of Ranvier or large myelinated fibres above the neuroma were examined in the electron microscope (EM). Most fibres exhibited normal action potentials, but a few had a reduced excitability and small action potentials. Some fibres had increased membrane time constant and leak conductance and a markedly increased membrane capacitance. Most of the examined nodes of Ranvier exhibited abnormally large delayed K currents, which could be blocked with 4-aminopyridine (4-AP). The Na current was normal. In the EM most large cross-cut myelinated axons were markedly atrophic, particularly after long survival times. Evaginations from the paranodal region of these axons penetrated between the terminating paranodal myelin lamellae. The nodal axolemmal undercoating could be very prominent and in some cases the nodal axon was irregular. These findings show that large myelinated peripheral nerve fibres, which are chronically disconnected from their peripheral targets, exhibit specific structural and functional abnormalities of the nodes of Ranvier.
Amputation Stumps↗
Unmyelinated axons in the feline trigeminal motor root.
The trigeminal motor root was studied in the electron microscope at different proximodistal levels in eight adult cats. Counts at a level halfway between the trigeminal ganglion and the pontine junction showed that the root contains about 9% (n = approximately 300) unmyelinated axon profiles at this level. Small groups of unmyelinated axons occur on both sides of the PNS-CNS border, in the surrounding pia mater, and in perivascular spaces of the CNS compartment. Examination of serial sections from the PNS-CNS transitional region showed that some unmyelinated axons actually cross the PNS-CNS border. The functional significance of these fibres remains unknown.
Animals↗
On nerves and teeth in the lower jaw of the cichlid Tilapia mariae.
The anatomy of the teeth and tooth-related nerves in the lower jaw was examined in the cichlid Tilapia mariae. This was done in order to establish a basis for studies on dental neuroplasticity in a polyphyodont vertebrate. The region of interest was explored in specimens fixed by glutaraldehyde perfusion, and by using X-ray photography, maceration, scanning electron microscopy, gross dissection, and light microscopic examination of serial sections. The results show that the lower jaw carries some 60-65 functional teeth. In addition, numerous replacement teeth and tooth germs in various stages of development are located in a cavity in the dentary bone. Numerous nerve bundles are present in immediate relation to the dental follicles of tooth germs. Unerupted teeth do not contain light-microscopically discernible pulpal axons, but the pulps of functional teeth contain myelinated axons. Both perifollicular and pulpal nerve bundles derive from a nerve plexus, which is formed by branches from r. mandibularis trigemini. This nerve is easily accessible to experimental manipulation, where it courses through the adductor mandibulae muscular complex. Thus, the lower jaw of T. mariae seems to represent a suitable system for the study of tooth-nerve interactions in a polyphyodont species.
Animals↗
Remodelling of internodes in regenerated rat sciatic nerve: electron microscopic observations.
Twelve adult rats received a crush lesion of the left sciatic nerve in the upper thigh. Following survival times of 2 weeks to 6 months, the animals were perfused with glutaraldehyde. Longitudinal thin sections from regenerated nerve segments were examined by electron microscopy. At survival periods of 2 weeks to 1 month, exceptionally short internodes composed of a Schwann cell lacking myelin, a more or less wrinkled Schwann cell-myelin sheath unit, or Schwann cell cytoplasm containing lamellated bodies and lipid droplets, were found intercalated between conventional regenerated myelin sheaths. Such intercalated sheaths were always bordered by sites with a nodal differentiation. Although much less frequent, short distorted myelin sheaths were also found at regeneration times of 2 and 3 months, but they have not been found in sections from 6-month specimens. In the long-term regenerated nerves many paranodes were distorted by prominent myelin folds and some nodes of Ranvier exhibited abnormal axon-Schwann cell networks and adaxonal Schwann cell protrusions. These observations show that internodes in regenerated rat sciatic nerves are subject to extensive remodelling. This includes internodal shortening and nodal migration, myelin sheath breakdown and demyelination, elimination of redundant Schwann cells and nodal fusion. These morphological changes may have important physiological implications.
Animals↗
Myelin sheath remodelling in regenerated rat sciatic nerve.
Adult rat sciatic nerves were subjected to a crush lesion and allowed to survive during 2 weeks-11 months. Segments of regenerated nerve were removed from exsanguinated animals and subjected to physiological analysis and light microscopic examination of teased fibres. Application of the potassium channel blocking agent 4-aminopyridine (4-AP) to regenerated nerve segments had marked effects on action potential waveform and recovery properties. When applied to normal control nerves 4-AP had minimal effects. Examination of teased preparations from the same nerves revealed the presence of two classes of internodes along regenerated nerve fibres. A majority of conventional regenerated internodes exhibited lengths (L) of at least 150 microns. Maximal L reached about 350 microns after one month survival and 550 microns 10 months later. In the individual nerve the maximal L-values tended to increase with fibre size. Most convential regenerated internodes had L-values of 200-400 microns. In addition, scattered unusually short sheaths, with L-values of 10-150 microns, were found intercalated between conventional internodes. Some intercalated sheaths had a wrinkled irregular configuration and some lacked a light-microscopically distinct myelin layer. We suggest that the occurrence of unusually short and partly distorted sheaths along regenerated fibres reflects a nodal-internodal remodelling in response to longitudinal crowding. These sites might represent foci with aberrant functional properties, possibly accounting for the 4-AP sensitivity of regenerated nerve.
4-Aminopyridine↗
Presence of unmyelinated axons in the spinal root of the feline accessory nerve.
The spinal root of the accessory nerve was studied electron microscopically at different levels in 3 adult cats. It was found that this nerve contains several unmyelinated axons. In the main nerve trunk the proportion of unmyelinated axon profiles was 27% at the level of the foramen magnum. In juxtamedullary root fascicles near the PNS/CNS transition the proportion of unmyelinated axons was lower and these axons tended to occupy superficial positions in the fascicles. No intrafascicular unmyelinated axons were found in the immediate vicinity of the PNS/CNS transition but bundles of unmyelinated axons occurred in the surrounding pia mater. The findings suggest that unmyelinated axons in the spinal accessory nerve contribute to the pial vasomotor and/or sensory innervation.
Accessory Nerve↗
Myelinated non-axonal neuronal elements in the feline olfactory bulb lack sites with a nodal structural differentiation.
Myelinated dendrites in the external plexiform layer (EPL) of the feline olfactory bulb and myelinated axons in the lateral olfactory tract (LOT), were examined by transmission electron microscopy. The results show that the non-axonal myelin sheaths are extremely thin and short and that the number of myelin lamellae does not increase with increasing dendritic diameter. In myelinated LOT axons the sheaths tend to be thicker and the myelin lamellar number increases with axon diameter. Domains with node-like structural characteristics are not encountered along myelinated dendrites, neither between successive myelin sheaths nor where single sheaths terminate. The partly myelinated neuronal perikarya, which occur in the EPL, also lack node-like domains. In contrast, typical nodes are easily found in myelinated LOT axons. In the periglomerular region dendrites and neuronal perikarya are surrounded by non-compacted glial sheets. It is concluded that myelination and node formation are relatively independent events and that morphogenetic glial-neuronal interactions may give different results in different parts of the same neuron.
Animals↗
Axo-glial relations in the retina-optic nerve junction of the adult rat: electron-microscopic observations.
The retina-optic nerve junction (ROJ) was examined by electron microscopy in adult rats, with particular emphasis on the unmyelinated-myelinated nerve fibre transition. Both single sections and serial sections were used. The non-retinal part of the ROJ is covered by an extensively folded glia limitans, facing the choroidea, sclera and pia mater. The blood vessels within the ROJ follow a transverse course and are surrounded by unusually wide perivascular spaces with a glia limitans-like outer delimitation. The endothelial cells exhibit numerous pinocytotic vesicles on their abluminal aspect. In the unmyelinated part of the ROJ the axons are embedded in an extensive meshwork of fibrous astrocytic processes. Some unmyelinated axons exhibit patches of axolemmal undercoating with externally associated astrocytic processes. Typical oligodendrocytes are not found, but a few small dark glial cells of unknown identity can be observed. Atypical ensheathment and myelination of axons at this level by ectopic Schwann cells occurred in one case. In the transition segment of the ROJ a pattern similar to that along dysmyelinated axons is observed, including aberrant axo-glial contacts, unusually thin and short myelin sheaths, intercalated unmyelinated segments, distorted myelin termination regions, bizarre paranodes and myelin termination regions without associated nodally differentiated axolemma. Neither sheath length nor number of myelin lamellae is related to axon diameter in the transition region. Axon diameter tends to be somewhat larger at myelinated than unmyelinated levels of the same axon. We suggest that the unusual axo-glial relations in this region are due to a deficient proliferation and differentiation of oligodendroglial cells, and that the pattern of glial ensheathment in the ROJ might be a consequence of the locally deficient blood-brain barrier.
Animals↗
Axo-glial relations in the retina-optic nerve junction of the adult rat: freeze-fracture observations on axon membrane structure.
The axolemmal ultrastructure of nerve fibres within the retina-optic nerve junction (ROJ) from adult rats was examined by freeze-fracture electron microscopy. In the juxtaocular (proximal) region of the ROJ, all fibres are unmyelinated. The axons generally have a membrane ultrastructure similar to that of retinal nerve fibre layer axons, with a high density of intramembranous particles (IMPs) on the P-fracture face and a low density of IMPs on the E-face. However, along some axons in this region of the ROJ, localized aggregations of E-face IMPs are observed. At levels of the ROJ closer to the optic nerve proper, the unmyelinated fibres enter a transition zone in which the axons acquire myelin sheaths. By the distal boundary of the transitional zone (optic nerve proper), virtually all fibres are myelinated. Within the transitional zone, conventional axo-glial associations and axolemmal ultrastructure is present at nodes of Ranvier. In addition, atypical axo-glial relationships and atypical nodal segments are observed in this region. At some nodes, an isolated oligodendroglial process, the axolemma usually displays a paranodal-like ultrastructure. Finger-like oligodendroglial processes were also observed in association with non-nodal unmyelinated axon membrane. At these sites of association, the axon membrane tends to be indented and may have a paranodal-like morphology. Nodal axolemma may exhibit several atypical forms in the transition zone. At some nodes, the nodal axolemma has a low density of E-face particles. Also, nodes of extended linear length (approximately 2 micron) exhibit a lower-than-normal density of P-face IMPs. At heminodes, the axolemma immediately adjacent to the terminal loops lacks the usual nodal characteristics of high IMP density and high percentage of large particles. The results show that aberrant axo-glial associations accompanied by unusual ultrastructural characteristics of the axolemma are present in the ROJ of normal adult rats.
Animals↗