Macrophages and the nervous system.
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Biomedical subjects
V H Perry
Publications and source records attributed to V H Perry.
Poor growth of Mammalian motor and sensory axons into intact proximal nerve stumps.
Wallerian degeneration is very slow in the mouse strain now known as C57BL/Ola. Sensory axon regrowth following peripheral nerve lesions is very poor in these animals but motor axons succeed in reinnervating the distal nerve stump even while the majority of severed axons are still intact (Lunn et al., Eur. J. Neurosci., 1, 27 - 33, 1989). To see if motor axons could grow into a completely undegenerated portion of nerve, the proximal stumps of the peroneal and tibial nerves were sutured together in six BALB/c mice and the ability of large motor and sensory fibres from the tibial nerve to grow into the peroneal nerve was examined electrophysiologically in four of them. For the acute experiment the peroneal nerve was cut approximately 7 mm central to the point of suture to the tibial nerve. Both at 2 weeks and 7 weeks after surgery the size of the potential recorded in the ventral roots on stimulating the portion of peroneal nerve into which tibial axons were directed to grow was only approximately 8% of the potential recorded when the tibial nerve was itself stimulated. The potential recorded in the dorsal roots was only approximately 2%. Counts of axon numbers in electron micrographs showed a small but non-significant increase over normal in the number of unmyelinated axons in the peroneal nerves which had been connected to the tibial nerve in this way. It is concluded, in agreement with Langley and Anderson (J. Physiol., 31, 365 - 391, 1904), that axon growth into intact nerves is extremely limited in mammals and that the distal nerve stump of C57BL/Ola mice, although it degenerates very slowly, is not therefore equivalent to an intact peripheral nerve.
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Very Slow Retrograde and Wallerian Degeneration in the CNS of C57BL/Ola Mice.
Wallerian degeneration following peripheral nerve transection in C57BL/Ola mice is very slow in comparison to other strains of mice. We show that following optic nerve transection, the axons of retinal ganglion cells in C57BL/Ola mice undergo very slow Wallerian degeneration and that retrograde degeneration of the ganglion cell bodies is much slower than in other strains of mice. The results suggest that the gene product affecting Wallerian degeneration in the peripheral nervous system (PNS) also confers a greater resistance to degeneration on central nervous system (CNS) neurons.
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Tetanus toxin-induced seizures cause microglial activation in rat hippocampus.
Tetanus toxin (about 20 mouse LD50) injected into the ventral hippocampus of rats leads to brief seizures occurring intermittently over a period of weeks. Toxin injection leads to the appearance of activated microglia (detected with OX42 immunohistochemistry) in the hippocampus. After 7-14 days, many activated microglia are visible in CA1 area of dorsal hippocampus aligned with the pyramidal cell dendrites and having the morphology characteristic of 'rod cells'. Extensive cell loss is found in dorsal CA1, but not at the injection site, in about one third of injected rats.
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Tumor necrosis factor mRNA localized to Paneth cells of normal murine intestinal epithelium by in situ hybridization.
Paneth cells in normal murine small intestine contain TNF mRNA that is readily detectable by in situ hybridization, unlike resident macrophages in lamina propria, which are negative. Northern blot analysis of whole tissue shows the presence of mRNA that has the same electrophoretic mobility as TNF mRNA from activated macrophages. A low level of TNF bioactivity, but no immunoreactivity, was detected in normal small intestine, and TNF production in resting Paneth cells appears to be post-transcriptionally controlled. Typical leukocyte surface membrane markers were not found on Paneth cells, but were expressed by the surrounding lamina propria macrophages. Paneth cells are thus epithelial cells with leukocyte-like secretory potential that may be important in intestinal physiology and pathology.
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Pathways mediating resolution in the primate retina.
In recent years there has been a dramatic increase in knowledge of the anatomy of the primate retina that relates to the pathways involved in visual resolution. The density of cones at the fovea has been shown to have a surprising degree of individual variability and the cone distribution is asymmetric about the fovea with a greater density of cones in nasal than temporal retina. Information about the fine detail of our visual world is carried to the dorsal lateral geniculate nucleus of the thalamus in two parallel pathways. These pathways originate from two morphologically distinct types of ganglion cell; the M-ganglion cells project to the magnocellular layers, P-ganglion cells to the parvocellular layers. Different roles for the two types of ganglion cell in mediating spatial visual resolution have been proposed. These cannot be determined using available physiological and anatomical data.
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Evidence that the lamina cribrosa prevents intraretinal myelination of retinal ganglion cell axons.
In the majority of mammals axons of retinal ganglion cells are not normally myelinated intraretinally. To test the hypothesis that the lamina cribrosa normally prevents myelin-forming cells from entering the retina we have examined the axons of retinal ganglion cells in conditions where there is no lamina cribrosa. Following transplantation of fetal retinae to the midbrain of newborn rats we have shown that ganglion cell axons within the transplants subsequently become myelinated, providing further evidence that the intraretinal segment of a ganglion cell axon is not refractory to myelination if myelin-forming cells are allowed access. Thus, our results support the hypothesis that the lamina cribrosa normally prevents oligodendrocytes or their precursors from gaining access to the retina. A number of factors may be involved in restricting the migration and differentiation of myelin-forming cells but it is apparent that there is a correlation between the absence or paucity of myelination and the presence of locally increased permeability of the blood-brain barrier. We suggest that proteins derived from plasma may influence oligodendrocyte precursor migration and/or differentiation at these sites.
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A neurofibrillar staining method for retina and skin: a simple modification for improved staining and reliability.
A simple modification of a reduced silver-stain for neurofilaments is described. Using neutral pH, perfusion fixation, and heat treatment during postfixation this method greatly improves the quality and reliability of staining of ganglion cells in retinal wholemounts from primate and other species. In addition it permits the selective staining of some cell populations thought to be refractory to silver stains. The method also stains cutaneous receptors in thick sections of the glabrous skin.
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An investigation into the early stages of the inflammatory response following ibotenic acid-induced neuronal degeneration.
Injection of the excitatory neurotoxin ibotenic acid into the septum produces rapid destruction of neuronal cell bodies and accompanying gliosis. We have previously shown that following ibotenate-induced cell death this may also result in damage to healthy axons en passage (Coffey et al., Neurosci. Lett. 84, 178-184, 1988). We suggested that the axonal damage resulted from non-specific damage by recruited inflammatory cells. In this study we have further examined the phenotype of the cells involved in the inflammatory response in the rat. Immunocytochemical identification of cells in the region of the lesion site identifies them as being of haematopoitic origin and most of them have the phenotype of macrophages. The dramatic increase in their number following an ibotenate lesion is sensitive to irradiation of the body providing evidence that the majority are blood derived. The inflammatory response is accompanied by a loss of myelin and a breakdown of the blood-brain barrier in the region of the lesion site. We have shown that these two effects are consequences of the inflammatory response since reduction in the inflammatory response by prior irradiation will abrogate these two effects.
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The pattern of axonal degeneration in the peripheral nervous system varies with different types of lesion.
Degeneration of axons in the mouse sciatic nerve was examined using conventional silver staining and by noting the presence or absence of a compound action potential on stimulating the nerve distal to the point of crush or cut. The presence of myeloperoxidase-positive cells was also examined in frozen sections of the nerve. In all experiments the distal, disconnected segment was studied. Degeneration after crushing with fine watchmakers forceps always began in the most distal part of the nerve and proceeded in a distoproximal direction, from the nerve entry point into a muscle back to the crush site. Myeloperoxidase-positive cells were also recruited into the nerve starting at the distal rather than proximal (the originally injured) end. This result favours the view that degeneration is triggered by lack of trophic support from the cell body rather than entry of deleterious substances at the site of the injury, for the terminals furthest from both the source of supply and the injury are affected first. Degeneration following nerve section was always more rapid than after crushing. The rate of axonal sealing at the injury was, however, no slower than after crushing, so it does not seem likely that greater entry of possible degeneration-triggering material at the injury site is the explanation for this. Crush lesions in which the perineurium was also cut open and the blood supply at the site was damaged, degenerated at the slower rate characteristic of simple crushes.(ABSTRACT TRUNCATED AT 250 WORDS)
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Heterogeneity in the distribution and morphology of microglia in the normal adult mouse brain.
We have examined the distribution of microglia in the normal adult mouse brain using immunocytochemical detection of the macrophage specific plasma membrane glycoprotein F4/80. We were interested to learn whether the distribution of microglia in the adult brain is related to regional variation in the magnitude of cell death during development and resulting monocyte recruitment, or whether the adult distribution is influenced by other local microenvironmental cues. We further investigated the possibility that microglia are sensitive to their microenvironment by studying their morphology in different brain regions. Microglia are present in large numbers in all major divisions of the brain but are not uniformly distributed. There is a more than five-fold variation in the density of immunostained microglial processes between different regions. More microglia are found in gray matter than white. Particularly, densely populated areas include the hippocampus, olfactory telencephalon, basal ganglia and substantia nigra. In comparison, the less densely populated areas include fibre tracts, cerebellum and much of the brainstem. The cerebral cortex, thalamus and hypothalamus have average cell densities. There was no simple relationship between the amount of developmental cell death and the adult distribution of microglia. An estimate of the total number of microglia in the adult mouse brain, 3.5 x 10(6), is comparable to that found in the liver on a weight for weight basis. However, microglia possess up to twice the surface area of membrane of Kupffer cells, the large resident macrophages of the liver. The proportion of cells that were microglia varied from 5% in the cortex and corpus callosum, to 12% in the substantia nigra. Microglia vary in morphology depending on their location. They were broadly classified into three categories. Compact cells are rounded cells, sometimes with one or two short thick limbs, bearing short processes ("bristles"). They resemble Kupffer cells of the liver and are found exclusively in sites lacking a blood-brain barrier. Longitudinally branched cells are found in fibre tracts and possess several long processes which are usually aligned parallel to, or more occasionally perpendicular to, the longitudinal axis of the nerve fibres. Radially branched cells are found throughout the neuropil. They can be extremely elaborate and there is wide variation in the length and complexity of branching of the processes. There was no evidence of monocyte-like cells in the adult CNS. The systematic variation in microglial morphology provides further evidence that these cells are sensitive to their microenvironment.
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Schwann cells promote the survival of rat retinal ganglion cells after optic nerve section.
Schwann cells (SCs) are known to play an important role for the regeneration of mammalian peripheral nerves. Their effect is likely due to the production of neuronotrophic and/or supportive factors. Here we study the effect of intraocular transplant of SCs on the survival of rat retinal ganglion cells (RGCs) after the intracranial section of the optic nerve. SCs were injected intraocularly in adult hooded rats. Surviving RGCs were retrogradely labeled with horseradish peroxidase applied to the proximal stump of the optic nerve. Results show that intraocular transplants of SCs promote the survival of a large number of RGCs for periods as long as 9 and 14 weeks after optic nerve section. In experimental retinae, surviving RGCs were 2- to 8-fold more numerous than in controls. This finding suggests that SCs are the source of factors that promote the survival of RGCs. Nerve growth factor is produced by SCs, and the intraocular injection of nerve growth factor has been previously shown to promote RGC survival. The rescuing effect of SCs on RGCs is greater than that obtained by intraocular injection of nerve growth factor. This greater effect may be due to the action of other neurotrophic factors produced by SCs or by transplanted SCs producing NGF in a sustained fashion.
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The anatomical basis of the caecocentral scotoma. New observations and a review.
It is shown that the 'papillomacular bundle' of optic nerve fibres, although a concept discussed frequently in the clinical literature, lacks a clear anatomical definition. It is suggested that the explanation for this is that the 'bundle' was originally described in autopsy studies of toxic amblyopia, not normal anatomy. The optic nerve fibre projection and vascular architecture of the caecocentral region of the retina is described. These anatomical features are discussed in relation to a number of possible anatomical explanations for the fact that a caecocentral scotoma is the characteristic field defect found in toxic amblyopia. We have been unable to identify a distinct anatomical feature which might explain this vulnerability but suggest that the problem has not as yet been clearly addressed by anatomists.
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Evidence that the Rate of Wallerian Degeneration is Controlled by a Single Autosomal Dominant Gene.
In a substrain of C57BL mice, C57BL/Ola, Wallerian degeneration in the distal segment of the severed sciatic nerve is extremely slow when compared to other mice. Despite this very slow degeneration in the distal segment regeneration of the motor nerves is not impaired. From suitable genetic outcrosses and backcrosses, the authors provide evidence that the rate of Wallerian degeneration in this strain is controlled by a single autosomal gene product. The authors have also shown that the rate of degeneration, in C57BL/Ola mice, is influenced by the environment in which the animals were bred and housed. Wallerian degeneration in the sciatic nerves of mice raised in isolators is slower than in those raised in a conventional animal house. This strain of mouse may prove to be of value in the understanding of nerve degeneration and regeneration.
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Evidence that Very Slow Wallerian Degeneration in C57BL/Ola Mice is an Intrinsic Property of the Peripheral Nerve.
We have described a mutant mouse, C57BL/Ola, in which Wallerian degeneration following peripheral nerve transection is very slow. Our previous results suggested that recruited monocytes play a role in rapid Wallerian degeneration. The nature of the mutation in C57BL/Ola mice is not known and we have investigated whether the defect is intrinsic to the nerve or due to a defect in the circulating monocytes. We have made chimaeric mice in which bone marrow from histocompatible mice, with rapidly degenerating nerves and normal monocyte recruitment, was used to reconstitute irradiated C57BL/Ola mice and vice-versa. A substantial degree of donor repopulation of the hosts was confirmed by measures of the levels of glucose-phosphate isomerase alloenzymes in blood and tissue samples from the two different strains. The rate of degeneration of the transected sciatic nerve was found to be host-dependent, providing evidence that the mutation affects cell populations intrinsic to the nerve and not the circulating monocytes. We provide additional evidence that the peripheral nerves of C57BL/Ola mice are different from those of other mice as they degenerate at a slower rate in vitro.
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Transneuronal retrograde degeneration of retinal ganglion cells after damage to striate cortex in macaque monkeys: selective loss of P beta cells.
We examined the retinae of two monkeys whose left striate cortex had been removed eight years previously and compared the transneuronally degenerated hemiretina of each eye with the normal hemiretina, and with the retinae of normal monkeys. All retinae were prepared as whole mounts. One from each pair was stained with Cresyl Violet; the other was reacted for horseradish peroxidase two days after placing pellets of the enzyme in the optic nerve. Measurements of ganglion cell density in the Nissl-stained retina of the contralateral right eye showed that approximately 80% of retinal ganglion cells were missing in the central 30 degrees of the degenerated hemiretinae. More peripherally the percentage loss was less extensive. Measurements of cell soma size and dendritic field size of peroxidase-labelled classified surviving cells in the degenerated temporal hemiretina of the ipsilateral eye showed them to be morphologically normal. In comparison with the normal hemiretina, however, the mean soma size at three selected eccentricities was larger than normal, suggesting selective loss of smaller ganglion cells. Classification of peroxidase-labelled ganglion cells in the normal and degenerated hemiretinae revealed that the population of P beta cells was reduced by as much as 85% in the degenerated region. There was comparable change in the density of P alpha or P gamma cells. The degeneration of the great majority of P beta cells, which are believed to be the morphological substrate of ganglion cells with small and colour-opponent receptive fields, must set limits on the visual sensitivity and discrimination that survive damage to striate cortex.
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Microglia in retinae transplanted to the central nervous system.
Retinae from fetal rats and mice were transplanted to the brains of neonatal rats: retinae from fetal rats were transplanted to the brains of adult immunodeficient nude mice. Using immunocytochemistry with monoclonal antibodies directed against cell surface antigens on macrophages and lymphocytes, we examined the leukocyte populations in transplants. We have shown that the transplants become populated by macrophages which have the morphology and phenotype of microglia. Furthermore, we have shown that in xenogeneic transplants most, if not all, of these cells are derived from the host. The microglia in the transplant retinae are more numerous and less precisely distributed when compared to normal retinae. Some microglia, particularly those associated with large blood vessels, express antigens typical of reactive microglia, including Class II antigens. We find that large numbers of macrophages and microglia are associated with the outer segments of the photoreceptors. In the absence of the retinal epithelium the macrophages may phagocytose discs shed from the outer segments of rods. We suggest that microglia derived from the host may be an important component of the instability of xenogeneic grafts.
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Microglia in the neurohypophysis associate with and endocytose terminal portions of neurosecretory neurons.
The rat neurohypophysis contains a population of microglial cells, the majority of which occupy a pericapillary position in the resting gland. The microglia are immunocytochemically identifiable by the presence of macrophage-associated antigens and resemble microglia of the CNS. Morphometry at light and electron microscopic levels reveals that such cells constitute approximately 19% of the intrinsic cell population, excluding the endothelial cells. Two other populations of neurohypophysial glial cells, parenchymatous pituicytes and fibrous pituicytes, do not express macrophage-associated antigens. The microglia have long processes which surround and, in some cases, engulf apparently viable portions of the magnocellular neurosecretory nerve terminals. A sequence of stages of selective endocytosis and degradation of the engulfed nerve terminals can be visualized within pericapillary microglia. Some phagosomes and secondary lysosomes contain morphologically intact neurosecretory granules; others contain partially destroyed neurosecretory granules or amorphous material all of which are identifiable as originating from the magnocellular neurosecretory terminals by their immunoreactivity for oxytocin- or vasopressin-neurophysin. This finding indicates a novel role for the microglial cells in remodelling terminal aborizations of neurosecretory neurons and in processing or degrading hormones and peptides they contain. Because of their close and selective associations with other cellular elements of the neurohypophysis, any substances produced by microglia also have the potential to influence hormone secretion, pituicyte proliferation and neurohypophysial vasculature.
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