Biomedical subjects

R Linden

Publications and source records attributed to R Linden.

At least 55 records · Page 3Linked to original sources

PubMed1994

The survival of developing neurons: a review of afferent control.

Developmental cell death is a major event of neurogenesis, and emphasis has systematically been placed on the roles of either the peripheral targets or central postsynaptic neurons in the control of neuronal survival. In this article, the main types of experimental design used to test the control of neuronal death by the afferent supply are compared with analogous data indicating neurotrophic support by the targets. It is argued that targets and afferents may have equivalent roles and interact in the control of neuron numbers during development of the vertebrate nervous system. Possible mechanisms of anterograde trophic control include contact-mediated cell interactions, activity-dependent processes mediated by neurotransmitters or neuromodulators, modulation of the levels of cytoplasmic free calcium and the involvement of neurotrophic factors.

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PubMed1994

Apoptosis in the developing retina: paradoxical effects of protein synthesis inhibition.

Cell death by apoptosis is usually characterized as an active process that requires protein and RNA synthesis. The requirement of protein synthesis for the degeneration of ganglion cells and other cell types was studied in neural retinae explanted from the eyes of newborn rats. Ganglion cells were detected by the presence of retrogradely transported horseradish peroxidase injected into the superior colliculus. Apoptotic cells were recognized by their condensed and deeply stained chromatin. The data show that the death of ganglion cells, whose axons are damaged when preparing the explants, is blocked or delayed by protein synthesis inhibitors. In contrast, the blockade of protein synthesis produced cell death with apoptotic morphology in the neuroblastic layer of the same retinae. The results suggest the operation in the developing retina of both a program of apoptosis dependent on the synthesis of killer proteins, and a latent mechanism of apoptosis that is normally blocked by repressor proteins.

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PubMed1993

Neuritogenesis of retinal ganglion cells is differentially promoted by target extract.

Labeled retinal ganglion cells from neonatal rats extended neurites in dissociated cell culture as a cell type-specific response to the influence of a superior collicular extract. The molecule responsible for this neuritogenic effect is soluble and non-dialysable (> 12 kDa). Nerve growth factor had a neuritogenic effect both on ganglion cells and other types of retinal cells.

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PubMed1993

Trophic factors produced by retinal cells increase the survival of retinal ganglion cells in vitro.

The naturally occurring neuron death of normal development has been shown to depend on trophic factors produced and released by target cells. It has also been shown that the afferent supply and local interactions play a role in the control of this degenerative phenomenon. We studied the effect of trophic factors produced by intrinsic retinal cells on the survival of retinal ganglion cells in vitro. Retinae of newborn hooded rats were retrogradely labelled with horseradish peroxidase injected into the superior colliculus to permit the identification of retinal ganglion cells in culture. We tested the effect of conditioned media either from aggregates or from explants of retinal cells from neonatal rats on the survival of ganglion cells in vitro. Our results showed that both conditioned media increased the survival of these cells. The trophic activity was dose-dependent, was maintained after dialysis against a 12 kDa membrane, was abolished by heating at 56 degrees C for 30 min, and was not found in conditioned medium from cerebral cortical explants. Conditioned medium obtained without fetal calf serum presented the same trophic effect. These results suggest that the local control of developmental neuron death by intrinsic retinal cells may be mediated by neurotrophic factors.

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PubMed1993

Intraretinal neurotrophic activity prevents the degeneration of ganglion cells in retinal explants.

The degeneration of ganglion cells was studied in neural retina explanted from the eyes of newborn rats. The ganglion cells were detected by the presence of retrogradely transported horseradish peroxidase injected into the superior colliculus. The time course of cell death among the axotomized ganglion cells in the explants was similar to that found in vivo after axotomy in neonatal rats. The effect of culture media conditioned with retinal cells from either newborn rats or chick embryos was tested on the survival of ganglion cells in the explants. Both conditioned media increased 2- to 3-fold the survival of rat retinal ganglion cells after 2 days in culture. The data show that soluble trophic factors released by retinae of distinct species can influence the survival of ganglion cells within their histotypic microenvironment.

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PubMed1992

Evidence for a developmentally regulated neurotrophic activity from chick retina affecting the survival of retinal ganglion cells from newborn rats.

The effect of conditioned medium from aggregates of chick embryo retinal cells was tested on the in vitro survival of retinal ganglion cells from newborn rats. Ganglion cells were identified by the detection of retrogradely transported horseradish peroxidase injected bilaterally into the superior colliculus. Culture medium conditioned with chick embryo retinae was tested on monolayers of rat retinal cells with plating densities ranging from 0.5 to 4 x 10(5) cells/cm2. In all cases the conditioned medium significantly increased the survival of ganglion cells after 2 days in culture. Conditioned media from embryonic days 8 to 16 (E8 to E16) presented neurotrophic activity, with the greatest effect occurring at E10-E12. The conditioned medium had no effect on the adhesion of rat retinal cells. The data suggest that chick retinal cells produces soluble trophic factors which can influence the survival of rat retinal ganglion cells in vitro. Furthermore, the release of this neurotrophic activity by chick retina seems to be developmentally regulated.

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PubMed1991

Evidence that the relative densities of afferents from both eyes control laminar distribution and binocular segregation of retinotectal projections in rats.

In the superior colliculus of normal rodents the crossed retinal projection overlaps the uncrossed projection. The present study describes an abnormal laminar distribution and binocular segregation of the retinotectal afferents induced after the experimental enlargement of the uncrossed retinotectal pathway in pigmented rats. Intraocular injections of anterograde tracers were used to investigate the topographic and laminar organization of retinotectal projections in adult rats given unilateral optic tract lesions at birth. These lesions are known to increase the number of ipsilaterally projecting ganglion cells in the opposite retina. The uncrossed retinal projection to the remaining superior colliculus forms an abnormal band of terminal labeling at the superficial half of the stratum griseum superficiale, markedly different from the laminar distribution of this pathway in unoperated controls. This abnormal uncrossed projection has its maximum density at the rostrolateral quadrant of the tectum. Within this region, the crossed retinotectal projection retracts from the surface of the superior colliculus, leading to partial binocular segregation. The results suggest that both the laminar distribution and the experimental binocular segregation of retinotectal afferents depend on the balance of the densities of the converging pathways from both eyes in the superior colliculus.

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PubMed1991

Axon orientation and axo-dendritic polarity of retinal ganglion cells during postnatal development in the rat.

The axon orientation and axo-dendritic polarities of ganglion cells were investigated in the retinae of developing and adult rats labeled with retrograde tracers. The cells were classified as either regular, if both parameters corresponded to those found among the majority of ganglion cells in the retina of adult rats, or irregular, if either axon orientation or axo-dendritic polarity, or both, failed to follow the norm of adult retinae. The number of regular cells declined from 118,000 to the adult value of 63,000 during the first 5 days following birth, while the number of irregular cells remained stable at 90,000-100,000 during this period and declined thereafter to 46,000. These data suggest that the geometry of neurites within the retina affect the selective elimination of ganglion cells during postnatal development in rats.

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PubMed1990

Cell death and interocular interactions among retinofugal axons: lack of binocularly matched specificity.

Naturally occurring ganglion cell death has been attributed to competitive interactions among axons at their targets during development of the retinofugal pathways. The present study is concerned with the hypothesis that interocular interactions leading to ganglion cell death are restricted to binocularly conjugate terminals in the optic nuclei. We tested this hypothesis in newborn rats by making localized retinal lesions, which denervate a restricted portion of the contralateral optic targets. When these rats reached adulthood, the ipsilaterally projecting ganglion cells of the intact eye were then studied following retrograde labeling with horseradish peroxidase. Results were compared with those from a normal, control group and from rats that had one eye removed on the day of birth. In those retinal loci binocularly conjugate to the lesion in the opposite eye, no localized cell rescue could be found among the ipsilaterally projecting ganglion cells. The same retinal loci, however, showed clear cell rescue after contralateral enucleation. Independent, anterograde, studies of the ipsilateral retino-collicular projection verified that lesions of equivalent size to those used in the retrograde study reliably create aberrant expanded uncrossed terminal fields. The present data suggest that the interocular interactions involved in the diminished ganglion cell loss which follows monocular enucleation are not dependent on topographically specific binocular matching. The phenomena of naturally occurring cell loss and of retinotopically specific interocular interactions may therefore be independent during normal development.

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PubMed1990

Control of neuronal survival by anomalous targets in the developing brain.

Described here is an aberrant parabigeminothalamic projection that follows neonatal lesions of the superior colliculus in rats, with evidence that this anomalous projection may sustain a normal number of neurons in the parabigeminal nucleus after early removal of the latter's tectal target. The aberrant projection was traced radioautographically to the tectorecipient zone of the lateral posterior nucleus after an injection of tritiated amino acid in the parabigeminal nucleus. Histochemical staining for cholinesterase revealed an anomalous patch of high enzyme activity in register with both the aberrant parabigeminothalamic projection and an abnormal retinal projection that also follows tectal lesions. Histochemical staining after either binocular enucleation or a tegmental lesion made simultaneous with the tectal ablation showed that the anomalous enzyme patch is a reliable marker of the aberrant parabigeminothalamic projection. It was also shown that the retinal projection is not needed for the formation of the anomalous parabigeminothalamic pathway. Ablation of the superior colliculus at birth failed to produce a net cell loss in the contralateral middle division of the parabigeminal nucleus after the period of natural neuronal death. Lesions extending toward the anomalous terminal field in the lateral posterior nucleus, however, prevented the survival of a normal number of neurons in the parabigeminal nucleus. When the unilateral tectal ablation was made together with a lesion of the ipsilateral posterior neocortex that produced cell loss in the thalamus, the number of neurons remaining in the middle division of the contralateral parabigeminal were linearly related to the cell content of the lateral posterior nucleus. We conclude that the anomalous target in the tectorecipient zone of the lateral posterior nucleus effectively replaces the normal projection field in the superior colliculus, with regard to the trophic requirements for neuronal survival during development of the parabigeminal nucleus.

Acetylcholinesterase↗

PubMed1990

The pearl mutation accelerates the schedule of natural cell death in the early postnatal retina.

The time of maximal occurrence of pyknotic nuclei in the retinal ganglion cell layer of postnatal pearl mutant mice is earlier than that in normal mice (Linden and Pinto 1985). Both ganglion and displaced amacrine cells and glia populate the ganglion cell layer. Thus, in order to show that ganglion cells themselves are affected, we counted the numbers of surviving axons in the optic nerve of postnatal day (PND) 0, 4, 12 and adult mice. On PND 0, pearl mutant mice had 139,000 +/- 2800 (SEM) optic axons, about 8% more than wild-type mice (128,000 +/- 1,700; p = 0.031) but on PND 4, pearl mutants had 24% fewer axons than wild-type mice (96,000 +/- 3700 and 119,000 +/- 4600, respectively; p = 0.008). Thus, pearl mutants lose nearly five times as many retinal ganglion cells as wild-type mice in the interval from PND 0 to 4. The number of axons present in adult mice was nearly equal (56,700 +/- 3200 for wild-type and 52,500 +/- 2700 for pearl mutants p = 0.37). We searched for evidence for changes in the schedule of cell death among other neurons of the retina by counting the number of pyknotic nuclei in the various retinal layers. On PND 4, pearl mutant mice had more pyknotic nuclei in the neuroblastic layer than wild-type mice (5000 +/- 400 and 3900 +/- 300, respectively; p less than 0.05). The time-course of the appearance of pyknotic nuclei in the outer nuclear layer differed for the two genotypes (ANOVA, F = 12.5, p less than 0.001). The most striking difference was a greater number of pyknotic nuclei on PND 20 for the pearl mutants (1300) than for wild-type (480; p = 0.002). However, the total number of photoreceptors in adults did not differ between the two genotypes (3.6 x 10(6) +/- 2.4 x 10(5) for wild-type and 3.7 x 10(6) +/- 3.3 x 10(5) for pearl; p greater than 0.8). These results, taken together, show that natural cell death occurs at an earlier time for retinal ganglion cells of pearl mutants, but that the total number of retinal neurons surviving to adulthood is not affected appreciably by the mutation.

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PubMed1990

Interactive effects of deafferentation and target removal on cell death in the parabigeminal nucleus of developing rats.

This study was designed to test the effects of simultaneous deafferentation and target removal on cell death in the parabigeminal nucleus. Bilateral lesions of the superior colliculus were made in newborn rats and neuron death was evaluated in the dorsal (PBd), middle (PBm) and ventral (PBv) divisions of the nucleus. When the results of the bilateral lesions were compared with the effects of unilateral lesions reported in a previous study simultaneous deafferentation and target removal were found to produce an increase in the rate of cell death greater than, and with a time course differing from that, predicted by the sum of the separate effects of removal of afferents or targets. These data suggest that the trophic effects of afferents and targets interact during the period of naturally occurring cell death.

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PubMed1990

Development of abnormal lamination and binocular segregation of retinal afferents onto the rat superior colliculus.

Unilateral optic tract lesions made in newborn rats produce abnormal retinotectal pathways on the opposite side. The present investigation was designed to study the development of the abnormal retinal projections in the superior colliculus using anatomical tracing methods. The aberrant uncrossed retinotectal pathway develops within the first postnatal week. In spite of this, the retraction of the crossed projection, which indicates binocular segregation, is of late onset. This indicates that the induced segregation of retinal inputs is not dependent on regressive events such as ganglion cell death and terminal field retraction. These data and the results of lid-suture experiments are consistent with a role for spontaneous retinal activity in the regulation of the plasticity of retinal projections to the rat superior colliculus.

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PubMed1990

Survival of retinal ganglion cells in vitro: the effect of conditioned medium from retinal cell aggregates.

The time course of degeneration of retinal ganglion cells was studied in vitro. We used the retinae of newborn hooded rats retrogradely labeled with horseradish peroxidase injected bilaterally into the superior colliculus to permit the identification of retinal ganglion cells in culture. We tested the effect of conditioned medium either from aggregates or from explants of retinal cells on the survival of the ganglion cells. Both conditioned media approximately doubled the survival of ganglion cells after 48-72 h in culture. Our data are consistent with the hypothesis that retinal cells produce soluble trophic factors that influence ganglion cell survival.

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PubMed1988

Afferent control of neuron numbers in the developing brain.

In this study we tested whether the quantitative matching of developing neuronal populations may depend on the size of the afferent supply. Partial deafferentation of the middle division of the parabigeminal nucleus (PBm) was produced before the period of naturally occurring cell death, by reducing the neuronal population of the superior colliculus following partial lesions or eye removal. The number of neurons surviving cell death in the PBm was linearly related to the number of its afferent neurons. This result supports the hypothesis that neurotrophic control by the afferent supply during the period of natural neuronal death is a major determinant of the number of neurons in the developing brain.

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PubMed1987

Dual control by targets and afferents of developmental neuronal death in the mammalian central nervous system: a study in the parabigeminal nucleus of the rat.

Natural and induced cell degeneration were studied in the mesencephalic parabigeminal nucleus of postnatally developing rats. Natural cell death in the normal parabigeminal nucleus had already started at birth, was maximal at 3 days, and proceeded with a declining rate until postnatal days 8-10 in the dorsal, middle, and ventral divisions that compose the nucleus. The number of neurons declined by approximately one-third between birth and postnatal day 15. A unilateral lesion of the superior colliculus made at birth modified this pattern. In the deafferented ipsilateral middle division, the rate of cell death was above normal from day 1 to day 10, and the number of neurons at day 15 was 60% less than in unoperated controls. In the contralateral middle division, in which at least some of the neurons were axotomized by the lesion, the rate of cell death increased at days 1-2 and decreased below normal at days 3-5. Induced changes in the number of neurons were consistent with this pattern, and at day 15 the number was similar to the control value. In the ipsilateral dorsal and ventral divisions, which suffered simultaneous axotomy and deafferentation, the rate of cell death increased in 2 peaks at days 1-2 and 4-6, and the numbers of neurons dropped to negligible values at day 15. The frequency curves of degenerating cells were poor predictors of the absolute changes in neuron numbers, and evidence was found of continued postnatal migration of neurons into the developing parabigeminal nucleus.(ABSTRACT TRUNCATED AT 250 WORDS)

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PubMed1987

Displaced ganglion cells in the retina of the rat.

The distribution, laterality of projection, and perikaryal sizes of displaced ganglion cells (DGCs) were examined in whole-mounted retinae after massive unilateral injections of horseradish peroxidase along the optic tract in pigmented rats. The DGCs were found predominantly in the lower temporal periphery of the retina. Nearly all DGCs labeled had contralaterally projecting axons. The sizes of the labeled DGCs spanned the range of ordinary ganglion cells, but few middle-sized DGCs were labeled. The results support the hypothesis that displaced ganglion cells are late-developing neurons that do not complete their migration toward the ganglion cell layer during retinal histogenesis.

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PubMed1987

Displaced amacrine cells in the ganglion cell layer of the hamster retina.

Neuronal populations were estimated in the ganglion cell layer (GCL) of the adult hamster retina. The total number of neurones averaged 128,000 in Nissl-stained whole-mounts. Following injections of horseradish peroxidase into the brain, an average of 72,000 cells were labeled (mostly above 8 micron in diameter), indicating that 56% of the neurones in the GCL are ganglion cells. Forty-one percent of the neurones (mostly below 8 micron diameter) of the GCL survived for 5 months after optic nerve transection at 12 days after birth. The results indicate that more than 40% of the neurones in the GCL of the hamster retina are displaced amacrine cells.

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