Search PubMed⌕ Search

Biomedical subjects

R D Lund

Publications and source records attributed to R D Lund.

At least 55 records · Page 3Linked to original sources
PubMed1998

Retinal degeneration and transplantation in the Royal College of Surgeons rat.

The Royal College of Surgeons rat provides a valuable animal model for examining the ontogeny of inherited or acquired photoreceptor degeneration and for assessing various treatment paradigms. Here we describe a sequence of events in which photoreceptor loss induces secondary changes that ultimately result in a progressive loss of retinal ganglion cells. The functional consequences of photoreceptor loss are described and compared with those observed in dystrophic animals that received grafts of pigment epithelial cells at an early stage in the degenerative process. The results of this work suggest that transplantation might slow or halt the progress of photoreceptor loss in certain human retinal degenerative conditions, provided suitable safeguards have been put in place.

Animals↗
PubMed1997

Parameters of transplant-mediated pupilloconstriction in rats with unilateral olivary pretectal lesions.

Embryonic retina, transplanted to the midbrain of neonatal rats, innervates the host brain and mediates a pupilloconstrictor response in the host eye. We hypothesise that there is a dynamic interaction between normal host and transplant photic input to the pupilloconstrictor centres. This study aims to characterise the nature of these interactions and determine the impact of experimental lesions on this reflex system. Pupillary diameter in normal rats is regulated by integration of intensity levels of the light delivered to the two eyes. The integration occurs at the primary input nucleus, the olivary pretectal nucleus, and at the output nucleus, the Edinger-Westphal nucleus. We have examined the pattern of integration of inputs delivered through the host eye and a retinal transplant placed over the midbrain at birth. Restriction of the site of integration to one olivary pretectal nucleus by ablating the contralateral nucleus causes a substantial enhancement of the transplant-mediated response and a major reduction in the host eye-mediated response. Although the pattern of change is quite similar to that seen between the two eyes of a normal animal after a similar lesion, the magnitude of improvement of the transplant response is much greater. The integration that occurs between transplant and host inputs is dynamic, and the efficacy of the transplant can be modulated by the competing host input. These results have implications for the use of neural transplants in degenerative diseases and might also offer insight into the limited functional recovery that occurs after neurological injury.

Animals↗
PubMed1997

Development of primary visual projections occurs entirely postnatally in the fat-tailed dunnart, a marsupial mouse, Sminthopsis crassicaudata.

We have examined the development of retinal projections in a diminutive polyprotodont marsupial, the fat-tailed dunnart, Sminthopsis crassicaudata. Here, we document the most immature mammalian visual system at birth described to date. At postnatal day (P) 0, the retinal ganglion cell layer has yet to form, and axons have not entered the optic stalk. By P4, the retinal ganglion cell layer could be distinguished at the posterior pole, and the front of growing axons extended one-third the length of the optic stalk, a distance of approximately 150 microm; a few pioneer growth cones had grown beyond the main axon group but had still to reach the midline. Axons had decussated at the optic chiasm by P10 to penetrate the base of the contralateral optic tract and, by P15, had reached the dorsal lateral geniculate nucleus (dLGN), superior colliculus (SC), and accessory optic system (AOS); ipsilaterally projecting axons matured slightly later. From P20, axons had reached the caudal SC both contralaterally and ipsilaterally and terminated throughout the depth of the retinorecipient layers. After P30, the projections gradually refined. Within the rostral dLGN, segregation into four contralateral and four ipsilateral bands occurred by P50, approximately 5 days after eye opening. The projection to the ipsilateral SC underwent refinement by P50, becoming restricted to its rostral pole, and presented as discrete patches within the stratum opticum. At birth, the dunnart visual system is comparable to early to midembryonic stages [embryonic day (E) 12, E14, E19, E24, and E30, respectively] in the mouse, rat, ferret, cat, and monkey. The extreme immaturity of the neonatal dunnart together with the observation that the entire development of the primary optic pathway occurs postnatally over a protracted period make this marsupial especially valuable for investigating factors that control pathway formation in the early developing mammalian primary visual system.

Age Factors↗
PubMed1997

Characterisation of the immune response in a neural xenograft rejection paradigm.

We have looked at both donor and host MHC expression in a neural xenograft rejection paradigm. Grafts of either mouse corpus callosum or an SV40 large T transformed astrocytic cell line were placed in the mid-brain of neonatal rats. Three weeks later graft rejection was induced by the application of a skin graft of the same donor origin. MHC expression in the neural graft and the host brain was examined histologically four and ten days after the animals had received a skin graft. Donor MHC expression was detected in the corpus callosal grafts at both time points and preceded host MHC expression and the lymphocytic infiltrate. The grafts of the transformed cell line could not be induced to express MHC antigens under the experimental protocol used nor were they rejected. The migratory patterns of the transformed cells were compared to the well characterised migration patterns of astrocytes from the corpus callosal grafts.

Animals↗
PubMed1997

Intraretinal transplantation to prevent photoreceptor degeneration.

There is great interest in the potential of transplantation to treat retinal degenerative diseases in humans; however, there are still fundamental questions to be addressed in experimental animal studies. We have concentrated on two of these using the Royal College of Surgeons (RCS) rat as a suitable animal model. Firstly, does the loss of photoreceptors lead to secondary changes in the inner retina, which might compromise any photoreceptor preservation strategy? Analysis has shown that there are not only histochemical changes in the inner plexiform layer but also degeneration of retinal ganglion cells. The latter, occurring as a result of a vascular event, appears to have a parallel in some human retinal degenerative diseases. Secondly, what are the functional implications of the progressive photoreceptor loss in the RCS rat and how may transplantation prevent or slow that process? A progressively enlarging visual field defect can be demonstrated in these rats which can be stabilized by transplantation of retinal pigment epithelial cells. There is also a loss or diminished performance in a variety of visual tasks, although the rate of deterioration depends on the task; this too can be limited by cell transplantation. Current results indicate an optimistic future for transplantation in human retinal degenerative disease, but also emphasize the many preparatory steps that still have to be made for a successful clinical outcome.

Animals↗
PubMed1996

Light induced EEG desynchronization and behavioral arousal in rats with restored retinocollicular projection by peripheral nerve graft.

Peripheral nerve (PN) was grafted to sectioned optic nerve and was bridged to the superior colliculus in adult rats. To test functional recovery of restored retinocollicular pathway, we examined cortical electroencephalogram (EEG) and behavioral arousal responses to light stimuli. In eight of 10 recording trials in PN grafted rats (n = 6) and in all of eight trials in normal rats (n = 5), cortical EEGs showed desynchronization to light stimuli. On the other hand, after bilateral sections of the optic nerve (n = 3) EEG desynchronization to light disappeared while it was induced by a white noise. Mean threshold duration of light for EEG desynchronization was significantly longer in the PN grafted rats (440 ms) than in normal rats (173 ms). In three of six trials in PN grafted rats (n = 4), and in four of eight trials in normal rats (n = 4), EEG desynchronization elicited by light stimulus was accompanied by behavioral arousal responses, whereas no behavioral arousal could be induced by light in blind rats (n = 3). These results strongly suggest that visual information processed through the restored retinocollicular pathway was further transmitted to the cerebral cortices and ultimately resulted in behavioral arousal of the PN grafted rats.

Animals↗
PubMed1996

Mechanism of retinal ganglion cell loss in inherited retinal dystrophy.

To study the inner retinal layers in RCS rats, which suffer major loss of retinal photoreceptors during the first 3 months of life, retinal ganglion cells (RGC) were labelled with fluorogold and their axons were immunoreacted with an antibody against neurofilaments. The retinal vessels were stained with horeseradish peroxidase and the RGC layer was stained with methylene blue. Animals more than 6 months of age showed areas devoid of fluorogold-labelled cells that extended from the optic disc to the periphery. The course of the RGC axons was also abnormal and showed tortuosities, dilatations and signs of abortive regeneration at sites where most inner retinal vessels cross the axons. We conclude that some months after photoreceptor degeneration has concluded in dystrophic animals, some retinal vessels compress the RGC axons and cause retrograde degeneration of their parent cells.

Animals↗
PubMed1996

Segregation of optic input in a three-eyed mammal.

Using a marsupial mouse, we have transplanted additional eye primordia to the midbrain at stages before host visual centers are normally innervated; transplant or host projections were later traced. In contrast to the normally continuous crossed retinocollicular input, both transplant and host projections were arranged as rostrocaudally aligned stripes or as discrete patches. We propose that competitive interactions between transplant and host axons have induced the discontinuous input.

Afferent Pathways↗
PubMed1995

Interactive events subserving the pupillary light reflex in pigmented and albino rats.

The consensual pupilloconstrictor response requires the intensity information that is delivered to each eye to be integrated to produce an averaged response such that the pupillary diameter in each eye is equal. Here we have examined how luminance information from each eye is integrated in the rat and where the integration occurs, using a pupillometry system to record pupillary diameter after illumination of one or both eyes. In albino rats the size of the uncrossed optic pathway to the pupilloconstrictor centre, the olivary pretectal nucleus, is reduced three-fold and there is a concomitant but less dramatic reduction in the size of the consensual response. Unilateral lesions of the olivary pretectal nucleus in pigmented rats restrict all optic input to the opposite pretectum. Stimulation of one or both eyes in these animals suggests that integration occurs not only at the level of the olivary pretectal nucleus, but also downstream in the Edinger-Westphal nucleus. Parallels with human studies and the opportunity to perform secondary lesions suggests the rat may provide a good model in which to study the substrates of the pupilloconstrictor response and mechanisms of integration of convergent parallel inputs in general.

Animals↗
PubMed1995

Pathfinding by retinal ganglion cell axons: transplantation studies in genetically and surgically blind mice.

Optic axons show a highly stereotypical intracranial course to attain the visual centers of the brainstem. Here we examine the course followed by axons arising from embryonic retinae implanted in neonatal ocular retardation mutant mice in which there had been no prior innervation of the visual centers. Retinae placed on the ventrolateral brainstem adjacent to the normal site of the optic tract send axons dorsolaterally toward the ipsilateral superior colliculus, which they innervate along with a number of other subcortical visual centers. Somewhat unexpectedly, axons also course ventrally to cross at the level of the suprachiasmatic nucleus or, less frequently, caudal to the mammillary body to follow the route of the optic tract and innervate contralateral visual centers. Retinae implanted along the course of the internal capsule emit axons that follow projection fibers through the striatum to innervate the lateral geniculate nucleus and other optic nuclei. These grafts also appear to project to the lateral part of the ventrobasal nucleus of the thalamus. The results show that prior existence of an optic projection is not necessary for axons derived from ectopic retinae to attain visual nuclei, not only on the side of implantation but also on the contralateral side of the brain. The cues that these growing axons follow appear to be stable temporally. The fact that axons can also follow highly anomalous routes, such as through the internal capsule, to attain target nuclei in the brainstem suggests that the normal optic pathway is not an obligatory route for optic outgrowth.

Animals↗
PubMed1995

Rejection of mesencephalic retinal xenografts in the rat induced by systemic administration of recombinant interferon-gamma.

Previous studies have shown that mesencephalic retinal xenografts can be induced to undergo rejection following various systemic and local manipulations of the host immune system. In each of these paradigms, the development of major histocompatibility complex (MHC) antigen expression on cells in and around the graft is correlated with the onset of rejection. We therefore examined the effect on graft viability of systemic administration of high-dose interferon-gamma a potent inducer of MHC antigen expression on cells within the brain. Postnatal Day 1 (P1) Sprague-Dawley rats received mesencephalic grafts of Embryonic Day 13 CD-1 mouse retina. Beginning at P30, one group of rats received daily injections of rat recombinant interferon-gamma intraperitoneally; litter-matched control animals received injections of vehicle alone. Rats were sacrificed on P51. Each of the animals with detectable grafts that had received interferon-gamma showed a strong rejection response characterized by perivascular cuffing with mononuclear cells in and around the graft and infiltration of the graft and the surrounding host brain by lymphocytes and MHC class I- and class II-antigen positive cells resembling reactive microglia. In contrast, only 2 of the 11 control grafts showed evidence of rejection. The rejection rate in the interferon-treated group was significantly higher than in the control group (Fisher's exact test, P = 0.0012). These results suggest that interferon-gamma is involved in the initiation and/or subsequent maintenance of the rejection response to cross-species transplants.

Animals↗
PubMed1995

The pupillary light response: functional and anatomical interaction among inputs to the pretectum from transplanted retinae and host eyes.

Pupilloconstriction to light can be mediated in rats through direct illumination of retinae previously transplanted to intracranial locations. Transplant-driven and normal pupillary light responses are stable under optimal testing conditions, and parameters describing the response can be quantified precisely. The present study demonstrates the interaction between transplant-driven and normal pupillary response patterns. When stimuli are presented concurrently to a transplanted retina and to the remaining eye in host rats, a greater degree of pupilloconstriction occurs than when either the transplanted or the host eye is illuminated independently. This suggests that transplant and host retinal inputs act in concert to determine pupil diameter. The second portion of this study investigates the pattern of retinal input to the pretectum to determine if a structural basis for such functional interactions may exist. Crossed and uncrossed retinal projections to the olivary pretectal nucleus occupy non-overlapping regions of this bilaterally represented nucleus in normal rats, with a greater number of optic axons directed to the contralateral olivary pretectal nucleus. Retinae transplanted to the midbrain of neonatal rats, from whom the contralateral eye had been removed, also project to the olivary pretectal nucleus at maturity. By contrast with the normal pattern of segregated retinal inputs, however, the terminal fields of transplant axons were found to overlap extensively with the retinal projection from the remaining host eye. In addition, the relative proportion of transplant axons directed to the ipsilateral and contralateral olivary pretectal nucleus varied among animals. The lack of spatial segregation between inputs from transplant and host sources and the relative proportion of ipsilateral and contralateral transplant axons together may represent a structural basis for the observed functional interactoin of these inputs to the neural circuit subserving pupilloconstriction to light. These features may also relate to the marked improvements in transplant-mediated responses that frequently occur when optic input from the remaining host eye is eliminated. The results presented here, together with our previous transplant studies, show that this preparation can be used to provide insight into more general questions as to the dynamic interactions that occur between converging sensory inputs in the generation of integrated output responses.

Animals↗
PubMed1995

The pupillary light response: assessment of function mediated by intracranial retinal transplants.

We have adapted a pupillometry measurement system to test the functional efficacy of retinae previously transplanted over the midbrain of neonatal rats in mediating a pupillary light reflex in the host eye. This has permitted us to examine factors influencing various parameters of the response, and to study transplant-mediated responses in comparison with responses mediated by way of the normal consensual pathway. Despite the unusual location of these transplanted retinae and the absence of supportive tissues normally associated with retinae in situ, it is clear that pupilloconstriction in the host eye can be elicited by transplant illumination. Under the optimal conditions here defined, response parameters for individual animals were stable with repeated testing over extended periods. When considered as individual cases, response amplitude, constriction rate and response latency were intensity dependent, although responses elicited by transplant illumination were less sensitive than normal, typically by 2-3 log units. Large-amplitude transplant-mediated pupillary responses could, however, be elicited repeatedly throughout long trains of stimuli, unlike normal responses, which rapidly failed to recover to baseline under similar test conditions. Finally, even though some cellular elements of the visual cycle are absent in transplanted retinae, pupilloconstriction in the host eye could be elicited repeatedly by transplant illumination as long as two years after transplantation took place. These observations indicate the applicability of this preparation as an assay for the effects of experimental manipulations on information processing and response plasticity in the visual system, and as a tool for examining, in general, the necessary conditions for optimal function of grafts that work by synthesizing and relaying neural signals.

Anesthesia↗
PubMed1994

Evidence for a tropic role of brain-derived neurotrophic factor in transplanted embryonic retinae.

Developing retinal axons must follow a stereotypic course directing them to the subcortical visual centres which on arrival they must recognise. Transplantation studies suggest that local substrate cues close to the surface of the brainstem and diffusible factors emanating from the target region are important. To test a role for diffusible factors, we transplanted retinae to the cerebral cortex and have shown that outgrowth can be promoted by BDNF secreting fibroblasts.

Animals↗
PubMed1994

The anatomical substrates subserving the pupillary light reflex in rats: origin of the consensual pupillary response.

While the olivary pretectal nucleus has been shown to be central to the pupillary constriction response in rats, it is not at all clear at which level the consensual response is generated. To examine this we have investigated the efferent projections of this nucleus, as well as the effect of unilateral lesions of the olivary pretectal nucleus, on the direct and consensual pupillary light reflexes. The results demonstrate that the olivary pretectal nucleus projects bilaterally to the Edinger-Westphal nucleus, as well as to the nucleus of the posterior commissure, which itself projects bilaterally to the Edinger-Westphal nucleus. The olivary pretectal nucleus also projects to the ipsilateral ventral lateral geniculate nucleus. Unilateral lesions of the olivary pretectal nucleus decrease, but do not abolish, the direct and consensual pupillary light reflexes by as much as 66%. Since some degree of consensual response remains, this is likely to be due to the bilateral projection from the olivary pretectal nucleus, either directly or indirectly through the nucleus of the posterior commissure, to the Edinger-Westphal nucleus. These results show that while the bilateral projection from the olivary pretectal nucleus to the Edinger-Westphal nucleus contributes to the consensual pupillary light reflex, the bilateral retinal projection to the olivary pretectal nucleus is the more determinant component of the pathway. In addition to providing insights into the anatomical substrates of the pupillary response, this work also provides a background to ongoing studies of the retinal graft-mediated pupillary light reflex, as well as serving as a model of a relatively simple reflex system.

Animals↗
PubMed1994

Visual information processing by intracerebral retinal transplants in rats.

We have developed a simple system involving the implantation of retinae over the midbrain of rodents to examine whether, in a clearly defined system such as the primary optic pathway, it is possible to re-create circuits lost as a result of injury or developmental disorder. For much of the work, immature rat hosts have been used, in part to maximise optimal conditions and to provide a baseline for similar transplants in adults. In this review we summarise the sequence of studies that has led us to the conclusion that transplanted retinae are capable not only of differentiating and responding to light but also of relaying luminance information to visual centres of the host brain where appropriate behavioural responses are elaborated.

Animals↗