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Biomedical subjects

G M Bray

Publications and source records attributed to G M Bray.

At least 37 records · Page 2Linked to original sources
PubMed1991

Degenerative and regenerative responses of injured neurons in the central nervous system of adult mammals.

In adult mammals, the severing of the optic nerve near the eye is followed by a loss of retinal ganglion cells (RGCs) and a failure of axons to regrow into the brain. Experimental manipulations of the non-neuronal environment of injured RGCs enhance neuronal survival and make possible a lengthy axonal regeneration that restores functional connections with the superior colliculus. These effects suggest that injured nerve cells in the mature central nervous system (CNS) are strongly influenced by interactions with components of their immediate environment as well as their targets. Under these conditions, injured CNS neurons can express capacities for growth and differentiation that resemble those of normally developing neurons. An understanding of this regeneration in the context of the cellular and molecular events that influence the interactions of axonal growth cones with their non-neuronal substrates and neuronal targets should help in the further elucidation of the capacities of neuronal systems to recover from injury.

Animals↗
PubMed1991

Regenerated synapses persist in the superior colliculus after the regrowth of retinal ganglion cell axons.

Synapse formation by retinal ganglion cell axons was sought in the superior colliculus of four adult rats 16-18 months after the optic nerve was transected and replaced by a peripheral nerve graft that guided regenerating RGC axons from the eye to the superior colliculus. The terminals of retinal ganglion cell axons were labelled by intravitreal injections of tritiated amino acids and studied by light and electron microscopic autoradiography. We found that (i) retinal ganglion cell axons had extended from the tips of the peripheral nerve grafts into the superior colliculus for approximately 350 microns; (ii) within the superior colliculus, some regenerated retinal ganglion cell axons became ensheathed by CNS myelin; (iii) retinal ganglion cell terminals formed asymmetric synapses with dendrites of neurons in the superficial layers of the superior colliculus, mainly the stratum griseum superficialis. Regenerated (n = 418) and normal retinal ganglion cell terminals (n = 1775) in the superior colliculus were compared in terms of their size (area, perimeter, and maximum diameter), contacts per terminal, contacts per 10 microns terminal perimeter, and post-synaptic structure contacted (dendritic spine, shaft, or soma). No statistically significant differences in the ultrastructural characteristics of the pre-synaptic profiles were apparent between the two groups. The post-synaptic structures contacted by axon terminals were similar in regenerated and control animals, although there were quantitative differences in the distributions of these contacts among dendritic spines and shafts. These results suggest that the regeneration of retinal ganglion cell axons in adult rats can lead to the formation of ultrastructurally normal synapses in the appropriate layers of the superior colliculus. The re-formed connections appear to persist for the life-span of these animals.

Animals↗
PubMed1991

Neuronal and nonneuronal influences on retinal ganglion cell survival, axonal regrowth, and connectivity after axotomy.

In contrast to the abortive regrowth that occurs when axons are interrupted in the adult mammalian CNS, exposure of injured CNS axons to the nonneuronal milieu of a peripheral nerve can lead to extensive axonal elongation. With the application of this experimental approach to the retinocollicular pathway in adult rodents, it has been possible to investigate the influences of neuron-glia and other interactions on the capacity of axotomized CNS neurons to survive injury, to elongate the distances necessary to reach specific targets, and to form connections in the CNS in adult rodents. The results of these investigations indicate that the changed glial environment provided by peripheral nerve grafts permits the guided regeneration of RGC axons to their CNS targets. Back in the CNS glial environment, regenerated axons penetrate their targets for short distances and re-form normal appearing synapses that can excite or inhibit postsynaptic neurons. Further studies will require a better understanding of intrinsic neuronal properties and of the interactions of these neurons with other neurons and with the cellular and noncellular components of the extraneural milieu.

Animals↗
PubMed1990

Synaptic connections made by axons regenerating in the central nervous system of adult mammals.

The restoration of connections in the injured central nervous system (CNS) of adult mammals is hindered by the failure of axons to grow back to their natural fields of innervation. Following transection of the optic nerve of adult rodents, the guided regeneration of retinal ganglion cell (RGC) axons along a transplanted segment of peripheral nerve (PN) has shown that these neurones retain their capacities to form well-differentiated synapses in both normal and abnormal targets. The main aim of this review is to describe the anatomical and functional characteristics of some of these connections and to suggest that their terminal distribution and morphology may be the result of a persistence in these targets of molecular determinants that influence normal connectivity in the intact animal.

Afferent Pathways↗
PubMed1990

Regrowth and connectivity of injured central nervous system axons in adult rodents.

The capacity of injured nerve cells to regrow and form terminal connections in the CNS of adult mammals was investigated in axotomized retinal ganglion cells (RGCs) of rodents whose optic nerves were substituted by an autologous segment of peripheral nerve. While many RGCs died after axotomy approximately 20% of the surviving RGCs regenerated axons several cm in length. Some of the regenerated RGC axons entered the superior colliculus where they arborized and formed well differentiated synapses that transynaptically excited or inhibited tectal neurons.

Animals↗
PubMed1989

Regenerated retinal ganglion cell axons can form well-differentiated synapses in the superior colliculus of adult hamsters.

To investigate in adult animals the distribution and differentiation of the synapses made by axotomized CNS neurons whose regenerating axons are guided back to their natural targets in the brain, we attached an autologous peripheral nerve (PN) graft 2-3 cm in length to the ocular stump of a transected optic nerve (ON) in adult hamsters, inserted the distal end of the graft into the superior colliculus (SC), and, 6-8 weeks later, labeled the retinal ganglion cell (RGC) axons that entered the SC with HRP orthogradely transported from the eye. By light microscopy, regenerated RGC axons extended from the graft into the retinorecipient layers of the SC for up to 500 microns, distances that approximate the lengths of normal RGC arbors. We compared 698 control and 758 regenerated HRP-labeled axon terminals from 4 intact and 4 experimental animals by electron microscopy. The structure of the regenerated RGC terminals, the type of synaptic contacts formed, the ratios of contacts to terminal perimeter, and the domains of the postsynaptic neurons contacted were similar to those of controls. These results indicate that regenerated RGC axons can form well-differentiated synapses in the SC. Morphological differences between the regenerated and control synapses were the larger size of some regenerated terminals, the greater mean length of the regenerated synapses, and the higher proportion of contacts with dendrites that contained vesicles. The synaptic differentiation attained by these reformed retinocollicular projections suggests that regenerating CNS axons and their target neurons in the adult mammalian brain may retain or reexpress certain molecular determinants of normal connectivity.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1988

Persistent retrograde labeling of adult rat retinal ganglion cells with the carbocyanine dye diI.

To study the retrograde labeling of intact and axotomized retinal ganglion cells (RGCs) over long periods of time, we applied the carbocyanine dye diI to the superior colliculi (SC) and dorsal lateral geniculate nuclei (dLGN) in adult albino rats and examined the retinas by fluorescence microscopy after different periods of survival. Retrogradely labeled RGCs, which were observed in the retinas as early as 3 days after application of the dye, gradually increased in density so that by 7 days more than 80% of the RGCs were labeled and by 30 days diI-labeled cell densities were similar to those observed after short applications of other tracers. Using short-term retrograde labeling with fast blue (FB) as an independent marker of RGCs, it was determined that these neurons remained labeled with diI for periods of up to 9 months without apparent leakage of the tracer to other retinal cells. In addition, diI labeling persisted in the somata of more than 80% of axotomized RGCs whose contact with the source of label had been interrupted for 3 months. Thus, we propose that retrogradely transported diI is a useful label for quantitative studies of neuronal populations, even after axotomy.

Amidines↗
PubMed1988

Influences of peripheral nerve grafts on the survival and regrowth of axotomized retinal ganglion cells in adult rats.

To investigate the role of extrinsic influences on the survival and growth of axotomized retinal ganglion cells (RGCs) in the mature mammalian CNS, both optic nerves (ONs) of adult rats were transected intraorbitally and, on one side, replaced by an autologous segment of peripheral nerve (PN) that had been left unconnected distally. The survival of RGCs and the regrowth of their cut axons into the PN grafts were assessed using morphometric techniques, neuroanatomic tracers, and immunologic cell markers to identify and count RGCs at times ranging from 15 d to 9 months. It was observed that (1) in the absence of a PN graft, more than 90% of the RGCs died by 1 month after axotomy; (2) between 1 and 3 months after axotomy, survival of RGCs in the PN-grafted retinas was enhanced 2-4-fold; (3) nearly 20% of the surviving RGCs regrew lengthy axons into the grafts; and (4) although the density of surviving RGCs in PN-grafted retinas decreased significantly between 1 and 3 months after axotomy, the densities of RGCs with axons extending into the graft remained relatively stable. These results confirm that in the adult rat retina, neuronal death is a major effect of axotomy near the cell soma. Although such lesions lead to the degeneration of many RGCs, we show that extrinsic influences introduced by the apposition of a PN segment at the time of severing the ON can rescue a substantial number of these neurons. Because the enhanced survival of many axotomized RGCs in the PN-grafted retinas appears to be limited to the first few weeks after injury, while those of RGCs that regenerate axons into the grafts do not show a parallel decline, it is possible that, in these experiments, neuronal viability depends on a spectrum of differently timed influences that may include the early diffusion of critical molecules arising from the graft and the subsequent establishment of more complex interactions with graft components.

Animals↗
PubMed1987

The use of peripheral nerve grafts to enhance neuronal survival, promote growth and permit terminal reconnections in the central nervous system of adult rats.

During both development and regeneration, the survival of neurones and the growth of axons are controlled by inherent neuronal properties, conditions in the axonal environment, and the establishment of appropriately timed and specific functional contacts. To study the effects of extrinsic influences on the survival, growth and connectivity of axotomized neurones in the mature mammalian CNS, we replaced the optic nerve in adult rats with segments of autologous peripheral nerve (PN) and used morphometric techniques, neuroanatomical tracer substances and immunological cell markers to examine retinal ganglion cells (RGCs), their axons in the PN grafts and their terminals in the superior colliculi (SC) of these animals. We observed that: (1) the survival of axotomized RGCs was enhanced by the PN grafts; (2) in the PN-grafted eyes, approximately 20% of the surviving RGCs regrew their axons into the grafts and (3) some of the RGC axons that regenerated along the PN grafts bridging the eye and the tectum re-entered the SC, arborized and made synaptic contacts with tectal neurones. It is not known if the terminal connections established between RGCs and cells in the SC are appropriate, functional or capable of influencing the long-term survival of their cells of origin.

Animals↗
PubMed1987

Axonal regeneration and synapse formation in the superior colliculus by retinal ganglion cells in the adult rat.

In adult rats, one optic nerve was transected and replaced by a 4 cm segment of autologous peripheral nerve (PN) that linked one eye and the superior colliculus (SC) along a predominantly extracranial course. Retrograde and orthograde studies with the tracers HRP or rhodamine-B-isothiocyanate (RITC), as well as immunocytochemical neuronal labels, indicated the following: (1) Regenerating axons from the axotomized retinal ganglion cells extended along the entire PN grafts, covering a distance nearly twice that of the normal retinotectal projection of intact rats. (2) Some of these axons penetrated the SC and formed terminal arborizations up to 500 microns from the end of the graft. (3) By electron microscopy, the arborizations of these regenerated axons in the SC were seen as small HRP-labeled axonal profiles that contacted neuronal processes in the SC; some of these contacts showed pre- and postsynaptic membrane specializations. These findings indicate that injured retinal ganglion cells in the adult rat are not only able to regrow lengthy axons, but may also form synapses in the SC.

Animals↗
PubMed1985

Axonal regeneration from GABAergic neurons in the adult rat thalamus.

Peripheral nerve grafts were inserted into the thalamus in 27 Sprague-Dawley rats. From 6 weeks to 15 months later, horseradish peroxidase (HRP) was applied to the extracranial end of each graft and sections of the brains reacted for peroxidase histochemistry. Of the thalamic neurons that were retrogradely labelled with HRP, more than 80% were located in the reticular nucleus of the thalamus (RNT), a distinct group of nerve cells that contain glutamic acid decarboxylase (GAD)-like immunoreactivity and are presumably GABAergic. By combining immunocytochemistry with HRP histochemistry, it was possible to confirm that the RNT neurons that had grown axons into the peripheral nerves grafts retained their GAD-like immunoreactivity. The apparent selectivity in their regenerative responses of RNT neurons to peripheral nerve grafts may relate to special properties of the neurons that did and did not grow into the grafts.

Animals↗
PubMed1984

Hypomyelination in the peripheral nervous system of shiverer mice and in shiverer in equilibrium normal chimaera.

In shiverer mice, the P1 component of myelin basic protein (MBP) is deficient in both the central nervous system (CNS) and peripheral nervous system (PNS) but compact myelin is more grossly defective in the CNS. In the PNS, myelin exhibits a normal periodic structure, and although examples of subtle abnormalities of shiverer Schwann cell ultrastructure have been described previously, myelin thickness has been reported as unremarkable when observed by light microscopy. We report a quantitative investigation of the myelin sheath thickness of shiverer Schwann cells in which a mild but apparently consistent hypomyelination of axons ensheathed by shiverer Schwann cells was observed. This abnormality was expressed both in the peripheral nerves of a homozygous shiverer mouse and in the shiverer Schwann cells populating the mosaic nerves of a mature shiverer in equilibrium normal mouse chimaera. In addition, multiple interlamellar gaps was found to be a highly consistent feature of shiverer myelin. These observations extend the description of the peripheral nerve defects expressed in shiverer mice and further define these abnormalities as direct consequences of the shiverer Schwann cells' intrinsic genotype. In light of these results, a significant role for P1 in the formation and/or maintenance of normal myelin in the PNS is suggested.

Animals↗
PubMed1984

Normal basal laminas are realized on dystrophic Schwann cells in dystrophic in equilibrium shiverer chimera nerves.

Multiple discontinuities are observed in the basal laminas of Schwann cells in mature dystrophic mice. To explore the pathogenesis of this abnormality we have exploited a dystrophic in equilibrium shiverer mouse chimera preparation in which both the basal lamina phenotype and the genotype of myelin-forming Schwann cells can be determined. If the basal lamina abnormality were to arise from an intrinsic deficiency of the dystrophic Schwann cell itself, only those Schwann cells of dystrophic genotype could express the mutant phenotype, whereas the coexisting population of shiverer Schwann cells should express typically normal basal laminas. No such distinction was observed; rather both dystrophic and shiverer Schwann cells were found to express relatively normal basal laminas and two pathogenetic mechanisms remain theoretical possibilities. The dystrophic Schwann cell population may be intrinsically defective but also may be rescued by obtaining the normal product of the dy locus synthesized by the coexisting shiverer cells. Alternatively, an extra Schwann cell deficiency existing within dystrophic mice may be normalized by shiverer cells and the normal intrinsic potential of both dystrophic and shiverer Schwann cells can then be realized. Regardless of the exact mechanism underlying these findings, some extracellularly mediated influence, emanating in vivo from shiverer cells, is capable of ameliorating the basal lamina deficiency typically expressed by dystrophic Schwann cells.

Animals↗
PubMed1983

Effects of crush injury on the abnormalities in the spinal roots and peripheral nerves of dystrophic mice.

Lumbosacral spinal roots and peroneal nerves in dystrophic and control mice were crushed and allowed to regenerate. Six weeks after crush injury, the dystrophic roots no longer showed the typical groups of unensheathed axons that characterize the uncrushed roots. Thus, the location of this ensheathment defect in the spinal roots cannot be the exclusive mechanism responsible for its development. Crush injury and regeneration also tended to correct a second abnormality in the peripheral nervous system of dystrophic mice: the discontinuities in the Schwann cell basal laminas. Because the regenerated nerves contained increased amounts of collagen, the results of this study support the evidence from tissue culture experiments that the extracellular matrix may be involved in the pathogenesis of these disorders. However, the outcome of the present in vivo experiments indicates that genetically normal fibroblasts are not required for this change to occur.

Animals↗
PubMed1982

Differentiation of the nodal and internodal axolemma in the optic nerves of neonatal rats.

Axon plasma membranes (axolemma) were studied by freeze-fracture electron microscopy at stages prior to and during myelination in the optic nerves of neonatal rats. In unensheathed axons, intramembranous particles associated with the internal (P) and external (E) leaflets of the axolemma increased in number before reaching a plateau (approximately 600/micron2 in both leaflets) at about 9 days postnatally. In newly myelinated fibres, by contrast, the distribution of particles was asymmetrical; fewer particles (approximately 200/micron2) were found on the E-face and greater numbers (approximately 1400/micron2) were present on the P-face, distributions similar to those observed in mature myelinated fibres. Node-like aggregations of particles were not found in unensheathed pre-myelinated axons nor were they present in axons presumed to be ensheathed by glial cytoplasm but not yet myelinated, although nodal specializations could be easily identified in fibres with only a few turns of compact myelin. These observations show first that there is a redistribution of particles in the P- and E-faces of the internodal axolemma coincident with the onset of myelination and secondly, that nodal specializations (represented by the increased densities of E-face particles) appear after ensheathment but before the formation of compact myelin in fibres of the rat optic nerve.

Aging↗