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Biomedical subjects

R D Lund

Publications and source records attributed to R D Lund.

At least 109 records · Page 6Linked to original sources
PubMed1989

Dopamine released from mesencephalic transplants restores modulation of striatal acetylcholine release after neonatal 6-hydroxydopamine: an in vitro analysis.

After chemical lesions which destroy the nigrostriatal dopamine pathway, transplants rich in dopamine neurons innervate the striatum and, with appropriate stimulation, drive host motor behaviors normally mediated by dopamine. We wished to determine whether dopamine released from the transplant also reinstated dopaminergic inhibition of striatal acetylcholine release. Three-day-old rat pups received bilateral intraventricular injections of 6-hydroxydopamine. Three days later cell suspensions prepared form embryonic ventral mesencephalon were injected unilaterally into the striatum. Tail pinch and amphetamine were able to elicit contralateral turning in many of these animals. Only those animals which rotated greater than or equal to 5 turns/min were included for further analysis. Subsequent assays indicated that 6-hydroxydopamine had depleted striatal dopamine to 4% of control and that the transplant had increased dopamine levels to 11% of control. Superfused striatal slices were stimulated (8 Hz, 1 min) and then exposed to amphetamine (10 microM, 3 min). The slice released dopamine, as measured by HPLC, and acetylcholine, as measured by tritium efflux after preincubation with [3H]choline. Moreover, the release of acetylcholine was inhibited by endogenous dopamine as indicated by the ability of sulpiride (1 microM) to increase tritium efflux. Striatal slices prepared from lesioned animals showed a reduction in dopamine overflow in response to both electrical stimulation (0.6% of control) and amphetamine (1% of control), and a decrease in the ability of sulpiride to increase electrically evoked acetylcholine overflow (12% of control). Transplantation partially restored the dopaminergic response to electrical stimulation (21% of control), and amphetamine (15% of control) and fully restored the sulpiride-induced increase in acetylcholine overflow (98% of control).(ABSTRACT TRUNCATED AT 250 WORDS)

Acetylcholine↗
PubMed1989

Development of dopamine innervation and turning behavior in dopamine-depleted infant rats receiving unilateral nigral transplants.

Three-day-old rats were bilaterally dopamine-depleted with 6-hydroxydopamine and 3 days later cell suspensions derived from the dopamine-rich ventral mesencephalic area were injected into the right rostral striatum. The transplants rapidly developed a substantial innervation of one striatum, so that by 15 days after transplantation (21 days of age) animals rotated away from the reinnervated side in response to amphetamine. The amount of turning correlated with the extent of innervation of the striatum as determined by tyrosine hydroxylase immunocytochemistry. By 25 days post-transplantation (31 days of age), animals turned in response to stress as well as amphetamine, although this later-developing phenomenon was not associated with any significant change in the extent of dopamine innervation. A second group of animals was bilaterally dopamine-depleted at 3 days of age, but transplantation with nigral cell suspensions was delayed until maturity. Partial reinnervation of the rostral striatum occurred with this delayed transplant paradigm, and turning to both amphetamine and stress commenced at 15 days post-transplantation. In contrast to animals receiving transplants shortly after lesioning, these animals began to turn spontaneously at about 20 days post-transplantation. The serotonin hyperinnervation that occurs following dopamine depletion in infancy was not altered by dopamine transplants made at either time. Results from both groups of transplant animals suggest that dopamine-rich transplants can provide substantial innervation that exerts some functional control over the striatum. This occurs despite the fact that neonatally dopamine-depleted rats, unlike adult-lesioned animals, survive quite well in the absence of striatal dopamine. However, the degree of incorporation into existing circuitry, and the types of regulation that result, may vary considerably depending on the age at which the tissue is transplanted.

Age Factors↗
PubMed1989

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.

Animals↗
PubMed1989

Light-evoked cortical activity produced by illumination of intracranial retinal transplants: experimental studies in rats.

We have investigated whether information relayed through intracranial retinal transplants can elicit responses in the visual cortex of host rats. Embryonic retinae were transplanted over the midbrain of neonatal rats. Four to eight weeks later, the transplants were exposed and stimulated with light flashes. This photic stimulation elicited both evoked responses and multi-unit activity in area 18a of the visual cortex. Pathway tracing studies using horseradish peroxidase showed that these responses are transmitted to the cortex via the superior colliculus, the lateral division of the lateral posterior nucleus of the thalamus, and possibly the medial portion of the dorsal lateral geniculate nucleus. It is suggested that this pathway may be involved in complex transplant-mediated visual behaviors.

Animals↗
PubMed1989

Retinal transplant-mediated learning in a conditioned suppression task in rats.

Retinae were transplanted from embryonic rats to a location over the midbrain of unilaterally anucleated newborn rats. At maturity, the rats were trained to "lever-press" for a food reward. By using a Pavlovian conditioned suppression paradigm, it was found that light delivered to the transplant could be recognized by the host rat as a conditioned stimulus, resulting in a reduced rate of lever pressing.

Animals↗
PubMed1989

The role of MHC and non-MHC antigens in the rejection of intracerebral allogeneic neural grafts.

Embryonic DA retinal allografts that have survived for prolonged periods after having been transplanted into the brains of neonatal BN rats can be induced to reject following peripheral sensitization with a DA skin graft. The results show that histocompatibility antigens play the major role in the rejection of grafts placed in the CNS and that a disparity between the retinal and skin grafts for MHC antigens induces a more severe rejection response than does a non-MHC antigen disparity.

Animals↗
PubMed1988

Behavioral and anatomical correlates of immunologically induced rejection of nigral xenografts.

Cell suspensions derived from the ventral mesencephalon of CD-1 mice were unilaterally transplanted into the striatum of neonatal Sprague-Dawley rats that had been bilaterally dopamine depleted. Thirty-eight percent of the grafts survived. Tyrosine-hydroxylase-immunoreactive neurons within the transplant innervated the host striatum with a dense fiber plexus. The grafts appeared to exert some degree of functional control over motor behavior in that these animals made contralateral rotations in response to amphetamine and tail pinch. In order to provide additional evidence that the motor behavior is associated with the transplant itself, the graft was removed. This was achieved by using a mouse skin graft to provoke an immunological response against the transplanted neural tissue. The immunological response resulted in the specific loss of the transplant with little or no damage to the surrounding neural tissue. The amount of rotation observed after tail pinch and amphetamine injection was severely affected by neural graft rejection. The loss of turning was associated most directly with the loss of tyrosine hydroxylase immunoreactivity within the transplant rather than with the massive reduction of tyrosine-hydroxylase-positive fibers in the ipsilateral host striatum. These data suggest that dopamine cells in mouse nigral grafts play an essential role in eliciting rotational behavior in neonatally dopamine depleted rats. They also show the value of skin grafting as a technique for specifically removing neural xenografts.

Animals↗
PubMed1988

Cotransplantation of embryonic mouse retina with tectum, diencephalon, or cortex to neonatal rat cortex.

Retinae from embryonic mice were transplanted to the occipital cortex of neonatal rats together with their normal target regions, tectum or diencephalon, from embryonic mice or rats. In control experiments, retinae were cotransplanted with embryonic rat occipital cortex. In over 80% of the experimental animals, both transplants differentiated and grew. Ganglion cells in the retinae cotransplanted close to tectum or diencephalon survived for at least 15 weeks. Their survival was associated with the development of a distinct optic fiber layer and outgrowth of axons from the transplanted mouse retina. Specific innervation of distinct patches within the cotransplanted rat tectum or diencephalon was demonstrated by the use of an anti-mouse antibody. The innervated regions, which could be as far away as 1.3 mm from the retinae, were correlated with cytological features of the cotransplanted tectum or diencephalon. By contrast, the host cortex was never innervated by the transplanted retinae. In the control animals in which the retinae were cotransplanted with occipital cortex and in four animals in which the cotransplants lay more than 2.7 mm apart, no ganglion cells were identified and there was no evidence of an optic fiber layer, outgrowth of axons, or innervation. These results support the idea that in order to survive, retinal ganglion cells need to innervate an appropriate target region. Further, the specific innervation of regions within the cotransplanted tectum or diencephalon suggests that these target regions are able to exert a tropic influence on the axons of retinal ganglion cells, even in the absence of many of the normal structure cues.

Animals↗
PubMed1988

Anatomical and behavioral correlates of a xenograft-mediated pupillary reflex.

Retinae from mouse embryos were transplanted to the midbrain of neonatal rats which were unilaterally enucleated at the time of transplantation. At maturity the host's remaining optic nerve was cut and the skull over the transplant was removed. Illumination of the transplant caused pupilloconstriction of the host eye, a response abolished by removal of the transplant or damage to the olivary pretectal nucleus which is the pupilloconstriction center of the brain stem. The degree of constriction correlated with the intensity of transplant illumination. Using mouse-specific monoclonal antibodies, we demonstrated that the grafts projected only to areas of the brain stem normally innervated by the eye. The density of label in the olivary pretectal nucleus did not, however, correlate with the briskness of the graft-mediated pupillary reflex. In summary, this study shows that ectopic neural xenografts are capable of making specific connections which can drive an appropriate response to a natural stimulus in the host animal. While important in showing the ability of transplants to make specific connections, this study also provides a simple assay system for examining conditions which may influence the efficacy of host innervation by the transplant.

Animals↗
PubMed1988

Instability of neural xenografts placed in neonatal rat brains.

Embryonic mouse retinae placed in neonatal rat brains differentiate normally, form appropriate connections with the host brain, and may survive for longer than 1 year. However, such grafts are susceptible to rejection, either spontaneously or after challenge. Advanced spontaneous rejection of the transplant was identified in about 10% of the animals. In addition, two circumstances have been defined in which mouse retinal grafts can be subsequently induced to undergo rejection. One is following placement of a mouse skin graft on the flank of a rat that has received a retinal transplant in the brain, and the other is following removal of a host eye. After each of these procedures, the neural grafts become infiltrated with lymphocytes and undergo degeneration. It is proposed that this system may provide a useful approach not only for studying the immunology and genetics of neural transplantation, but also for examining the circumstances that precipitate the degenerative events associated with certain autoimmune diseases of the central nervous system.

Animals↗
PubMed1988

Conditions for optic axon outgrowth.

A series of studies is described which show that retinal axon outgrowth can be stimulated by the close proximity of an appropriate target region. The suggestion is offered that, in normal development, optic axons first follow cues available at the surface of the brainstem, but once they reach a target region, ramify there in response to the presence of a target-derived factor.

Animals↗
PubMed1987

Role of the target in directing the outgrowth of retinal axons: transplants reveal surface-related and surface-independent cues.

In the present investigation we have examined whether retinal axons can be directed to the superior colliculus via an alternate route when they do not have access to their normal substrates along the optic tract. To address this issue we transplanted embryonic mouse retinae into the midbrain parenchyma and to various positions around the outer surface of the midbrain of newborn rats and then examined the development of projections from the transplanted tissue. The projections from cortical grafts placed in the midbrain were studied to determine whether axons from different classes of neurons respond to the same cues for outgrowth. When retinae were placed within the midbrain close to the cerebral aqueduct, axons projected dorsally to the superficial layers of the superior colliculus. Directed outgrowth was seen from the earliest time a projection could be detected and was independent of whether the superior colliculus still received host optic afferents. In contrast, the major projection from similarly placed cortical transplants was directed toward the ventral part of the midbrain. Deafferentation of midbrain corticorecipient areas did not affect the projection patterns from either type of graft. Projections from retinae placed more ventrally in the midbrain tegmentum could not be detected. However, retinae placed on the surface of the midbrain, even as far ventral as the cerebral peduncle at the level of the inferior colliculus, always had a projection to the superior colliculus that ran along the brainstem surface. These observations suggest that the superior colliculus exerts a positive influence on the growth of optic axons to the midbrain. However, while target cues appear to be able to support retinal axon growth through the midbrain parenchyma, their range appears to be limited, and at distances beyond the extent of their influence, optic fiber outgrowth occurs only over the surface of the brain. It is suggested, therefore, that there are both local surface-related and target-derived surface-independent cues that guide optic axons to the tectum in developing mammals.

Animals↗
PubMed1987

Specific target-directed axonal outgrowth from transplanted embryonic rodent retinae into neonatal rat superior colliculus.

We have investigated whether there is evidence of target-directed growth of retinal axons to the tectum, and whether the surface of the rostral brainstem is an obligatory substrate for growing optic axons by transplanting embryonic mouse retinae to the cerebral aqueduct of neonatal rats. Such retinae emit axons that grow dorsally through the brain parenchyma to reach the superficial layers of the superior colliculus either by running dorsally along the midline, or by following a dorsally directed, radially arching course through the brain parenchyma. Studies of the early outgrowth pattern from transplanted retinae, and comparison studies of the axonal outgrowth from similarly placed cortical grafts suggest that outgrowth of retinal axons is target-directed and specific to optic axons.

Animals↗