Showing papers by "Anders Björklund published in 1988"

Human fetal dopamine neurons grafted in a rat model of Parkinson's disease: immunological aspects, spontaneous and drug-induced behaviour, and dopamine release.

Abstract: We have used a rat model of Parkinson's disease (PD) to address issues of importance for a future clinical application of dopamine (DA) neuron grafting in patients with PD Human mesencephalic DA neurons, obtained from 65-8 week old fetuses, were found to survive intracerebral cell suspension xenografting to the striatum of rats immunosuppressed with Cyclosporin A The grafts produced an extensive new DA-containing terminal network in the previously denervated caudate-putamen, and they normalized amphetamine-induced, apomorphine-induced and spontaneous motor asymmetry in rats with unilateral lesions of the mesostriatal DA pathway Grafts from an 115-week old donor exhibited a lower survival rate and smaller functional effects As assessed with the intracerebral dialysis technique the grafted DA neurons were found to restore spontaneous DA release in the reinnervated host striatum to normal levels The neurons responded with large increases in extracellular striatal DA levels after the intrastriatal administration of the DA-releasing agent d-amphetamine and the DA-reuptake blocker nomifensine, although not to the same extent as seen in striata with an intact mesostriatal DA system DA fiber outgrowth from the grafts was dependent on the localization of the graft tissue Thus, grafts located within the striatum gave rise to an extensive axonal network throughout the whole host striatum, whereas grafted DA neurons localized in the neocortex had their outgrowing fibers confined within the grafts themselves In contrast to the good graft survival and behavioural effects obtained in immunosuppressed rats, there was no survival, or behavioural effects, of human DA neurons implanted in rats that did not receive immunosuppression In addition, we found that all the graft recipients were immunized, having formed antibodies against antigens present on human T-cells This supports the notion that the human neurons grafted to the non-immunosuppressed rats underwent immunological rejection Based on an estimation of the survival rate and extent of fiber outgrowth from the grafted human fetal DA neurons, we suggest that DA neurons that can be obtained from one fetus may be sufficient to restore significant DA neurotransmission unilaterally, in one putamen, in an immunosuppressed PD patient

Endogenous release of neuronal serotonin and 5-hydroxyindoleacetic acid in the caudate-putamen of the rat as revealed by intracerebral dialysis coupled to high-performance liquid chromatography with fluorimetric detection.

Abstract: Extracellular levels of endogenous serotonin (5-HT) and its major metabolite, 5-hydroxyindoleacetic acid (5-HIAA), were measured in the caudate-putamen of anesthetized and awake rats using intracerebral microdialysis coupled to HPLC with fluorimetric detection. A dialysis probe (of the loop type) was perfused with Ringer solution at 2 μl/min, and samples collected every 30 or 60 min. Basal indole levels were followed for up to 4 days in both intact and 5,7-dihydroxytryptamine (5,7-DHT) lesioned animals. Immediately after the probe implantation, the striatal 5-HT levels were about 10 times higher than the steady-state levels that were reached after 7-8 h of perfusion. The steady-state baseline levels, which amounted to 22.5 fmol/30 min sampling time, remained stable for 4 days. In 5,7-DHT-denervated animals, the steady-state levels of 5-HT, measured during the second day after probe implantation, were below the limit of detection (<10 fmol/60 min). However, during the first 6h post-implantation, the 5-HT output was as high as in intact animals, which suggests that the high 5-HT levels recovered in association with probe implantation were blood-derived. As a consequence, all other experiments were started after a delay of at least 12 h after implantation of the dialysis probe. In awake, freely moving animals, the steady-state 5-HT levels were about 60% higher than in halothane-anesthetized animals, whereas 5-HIAA was unaffected by anesthesia. KCI (60 and 100 mM) added to the perfusion fluid produced a sharp increase in 5-HT output that was eight-fold at the 60 mM concentration and 21-fold at the 100 mM concentration. In contrast, 5-HIAA output dropped by 43 and 54%, respectively. In 5,7-DHT-lesioned animals, the KCl-evoked (100 mM) release represented less than 5% of the peak values obtained for the intact striata. Omission of Ca2+ from the perfusion fluid resulted in a 70% reduction in baseline 5-HT output, whereas the 5-HIAA levels remained unchanged. High concentrations of tetrodotoxin (TTX) added to the perfusion medium (5-50 μM) resulted in quite variable results. At a lower concentration (1 μM), however, TTX produceda 50% reduction in baseline 5-HT release, whereas the 5-HIAA output remained unchanged. The 5-HT reuptake blocker, indalpine, increased the extracellular levels of 5-HT sixfold when added to the perfusion medium (1 μM), and threefold when given intraperitoneally (5 mg/kg). By contrast, the 5-HIAA level remained unaffected during indalpine infusion. Application of TTX (1 μM) under simultaneous 5-HT uptake blockade induced a decrease in 5-HT output by 62–71%. p-Chloroamphetamine (2.5 mg/kg, i.p.) induced a 12-fold increase in 5-HT release and reduced the 5-HIAA output by about 50%. The p-chloroamphetamine-induced increase in 5-HT release was 10 times lower in the 5,7-DHT-denervated striatum. Pargyline (75 mg/kg, i.p.) increased the extracellular levels of 5-HT 11-fold within 6 h, and reduced the 5-HIAA levels by 80%. The 5-HT receptor agonist, 5-methoxy-N,N-dimethyltryptamine (1 mg/kg, i.p.), produced an immediate reduction of about 50% in 5-HT release and a small (11 %) decrease in 5-HIAA output. It is concluded (1) that intracerebral microdialysis coupled to HPLC with fluorimetric detection provides a useful method for the study of extracellular 5-HT and 5-HIAA levels; (2) that steady-state levels of 5-HT and 5-HIAA recovered in the dialysis perfusate are neuronally derived, but these steady-state levels are reached only after a minimum of 7–8 h after probe implantation; (3) that changes in striatal extracellular levels of 5-HT are closely related to changes in serotonergic synaptic activity; and (4) that extracellular levels of 5-HIAA are a poor indicator of synaptic activity, and instead primarily reflect intraneuronal metabolism.

Human fetal dopamine neurons grafted in a rat model of Parkinson's disease: ultrastructural evidence for synapse formation using tyrosine hydroxylase immunocytochemistry

Abstract: Human fetal mesencephalic dopamine (DA) neurons, obtained from 6.5–9 week old aborted fetuses, were grafted to the striatum of immunosuppressed rats with 6-hydroxydopamine lesions of the ascending mesostriatal DA pathway. The effects on amphetamine-induced motor asymmetry were studied at various timepoints after grafting. At eight weeks, functional graft effects were not evident but after 11 weeks small effects on motor asymmetry could be monitored and rats tested 19–21 weeks after grafting exhibited full reversal of the lesion-induced rotational behaviour. Four rats were sacrificed at different timepoints between 8 and 20 weeks and the grafted DA neurons were studied in tyrosine hydroxylase (TH) immunocytochemically stained sections at the light and electronmicroscopic level. The grafts contained a total of 500–700 TH-positive neurons in each rat. In one rat sacrificed 8 weeks after grafting the grafted neurons were TH-positive but exhibited virtually no fiber outgrowth. In another rat, sacrificed after 11 weeks, a sparse TH-positive fiber plexus was seen to extend into the adjacent host neostriatum. Two rats sacrificed after 20 weeks both contained TH-positive neurons that gave rise to a rich fiber network throughout the entire host neostriatum, and this fiber network was also seen to extend into the globus pallidus and nucleus accumbens. Very coarse TH-positive processes, identified as dendrites in the electron microscope, projected up to 1.5–2.0 mm from the graft into the host striatum. Ultrastructural analysis revealed that the grafted neurons had formed no TH-positive synaptic contacts with host striatal neurons after 8 weeks, and at 11 weeks some few TH-positive synapses were identified. Twenty weeks after transplantation, abundant TH-positive synaptic contacts with host neurons were seen throughout the neostriatum, and such contacts were identified in the globus pallidus as well. Thus, the present study provides tentative evidence for a time-link between the development of synaptic contacts and the appearance of functional graft effects. Similar to the normal mesostriatal DA pathway, ingrowing TH-positive axons formed symmetric synapses and were mainly seen to contact dendritic shafts and spines. However, in comparison to the normal rat striatum there was a higher incidence of TH-immunoreactive boutons forming synapses onto neuronal perikarya. The TH-positive dendrites that extended into the host striatum were seen to receive non-TH-immunoreactive synaptic contacts, presumably arising from the host neurons. These results suggest that human fetal DA neurons are able to develop a reciprocal synaptic connectivity with the host rat when grafted to the adult brain. Grafting of human fetal DA neurons may therefore be expected to provide a means of restoring regulated synaptic DA release in patients with Parkinson's disease.

Comparison of growth and reinnervation properties of cholinergic neurons from different brain regions grafted to the hippocampus.

Abstract: Grafts of five different types of central cholinergic neurons, from the septal-diagonal band region, the nucleus basalis magnocellularis region (NBM), the striatum, the pontomesencephalic tegmentum of the brainstem, and the spinal cord, were compared with respect to their ability to grow and to reinnervate the cholinergically denervated hippocampal formation of adult rats. The areas were dissected from 14 to 15-day-old rat fetuses, and the same number of viable cells (35 X 10(4) from each of the different regions were stereotaxically injected as cell suspensions into the hippocampus of rats subjected to a transection of the intrinsic septo-hippocampal cholinergic pathways. At 17-19 weeks after transplantation, the various graft types differed considerably in their volume, the total amount of acetylcholinesterase (AChE)-positive fiber outgrowth, and the innervation pattern and morphology of the AChE-positive fibers growing into the host hippocampus. On average the NBM and spinal cord grafts had grown to become three to four times larger than the septal and the brainstem grafts, and 15-20 times larger than the striatal grafts. By contrast, the total ingrowth score of AChE-positive fibers in the host hippocampus from the septal grafts was about twice that of the NBM and brainstem grafts, about five times greater than the striatal grafts, and about six times greater than that of the spinal cord grafts. The large NBM grafts thus exhibited similar fiber outgrowth to the much smaller brainstem grafts, and the AChE-positive neurons of the grafted spinal cord grew very poorly into the hippocampus despite the fact that they survived very well. The innervation pattern and morphological features of the ingrowing AChE-positive fibers in the host hippocampus proper and in the dentate gyrus resembled those of normal rats in animals with grafts from any of the three forebrain regions (i.e., septum, NBM, or striatum), whereas ingrowth from the brainstem and spinal cord grafts were markedly abnormal with respect to both innervation pattern and fiber morphology. These results provide further evidence that the overall survival, growth, and fiber outgrowth of intracerebral neural grafts depend on interactions with the surrounding host tissue. Since the ability to reinnervate the previously denervated host target was greatest for the neuron type normally innervating that area, i.e., the septal-diagonal band neurons, we conclude that neuronal properties beyond the transmitter type are essential for the optimal performance of implanted neurons in intracerebral grafting experiments.

Transmitter expression and morphological development of embryonic medullary and mesencephalic raphé neurones after transplantation to the adult rat central nervous system. II. Grafts to the hippocampus.

Abstract: Suspensions of cells derived from the mesencephalic raphe or medullary raphe regions of the 13–14 day old embryonic rat brain were injected into the spinal cord of adult rats which had been previously denervated with 5,7-dihydroxytryptamine. At periods of up to 12 months after grafting, the spinal cords were taken for immunohistochemical analysis of 5-hydroxytryptamine (5HT), substance P (SP) and thyrotropin releasing hormone (TRH). In nearly all cases, surviving transplants were found. The grafts derived from mesencephalic raphe cells contained neurones which were immunoreactive to 5HT, or SP, but not both together. On average 4% of the total possible number of the available embryonic mesencephalic serotoninergic cells were found. A very dense outgrowth of 5HT positive fibres from the transplant was observed, extending up to 1.5 cm in both the caudal and rostral directions from the graft locus. Some SP immunoreactive fibres were also apparent near the implant. The grafts derived from the medullary transplant also contained 5HT-immunoreactive cells, comprising on average 25% of the total 5HT neurones available from the embryonic medullary primordium. In addition, neurones colocalizing 5HT together with SP and TRH were visible, closely reflecting the situation found in the medullary raphe in situ. Dense plexi of fibres containing 5HT-LI extended both caudally and rostrally up to 12–15 mm from the transplant. Outgrowth of SP and TRH varicose fibres was also demonstrable, although to a lesser degree than for 5HT. It was also possible to find many motoneurones surrounded by varicose fibres containing both 5HT and SP, in contrast to the situation with the mesencephalic grafts, where no such patterns of innervation were seen. The experiments indicate that the milieu of the spinal cord may compromise the survival of mesencephalic raphe 5HT neurones far more than of medullary serotonin cells. However, despite this effect on cell survival, the outgrowth of fibres from the remaining mesencephalic 5HT neurones was apparently unaffected by their ectopic position. Similarly, the transmitter content of both classes of raphe cells was largely unaltered, either by the transplantation process or by the environment into which they were placed. It is concluded that although the adult denervated spinal cord can selectively affect neuronal survival, it is incapable either of inducing in other serotoninergic cells placed within it the transmitter phenotype typical of medullary raphe neurones, or of causing those ectopically located 5HT cells to form connections appropriate to the descending serotonin fibres.

Fetal cortical cell suspension grafts to the excitotoxically lesioned neocortex: anatomical and neurochemical studies of trophic interactions.

Abstract: Publisher Summary Neural grafting has emerged as an interesting tool for the study of trophic neuron-target interactions in the central nervous system. This chapter describes a model for the study of trophic interactions in the adult neocortex based on extensive kainic acid (KA) -induced or Nmethyl-D-aspartate (NMDA) -induced cortical damage and subsequent intracortical suspension grafts of foetal cortical tissue. The chapter also presents neurochemical and basic morphological features of the KA lesion and the cortical suspension grafts. The fetal neocortical tissue, implanted in the form of multiple deposits of a dissociated cell suspension, can survive and differentiate in the depth of the KA- or NMDA-lesioned cortex of adult recipient rats. In adult rats, the neuron-depleted excitotoxically lesioned cortex provides a better growth environment for the fetal tissue than the non-lesioned one. Various observations indicate that the excitotoxic lesion may favor graft growth by the provision of both growth space and opportunities for trophic or connectivity interactions with the host brain. The anatomical studies of the lesioned neocortex with intracortical cell suspension grafts also indicate that several of the normal cortical inputs have the capacity to grow into the grafts. The chapter concludes that the excitotoxic cortical lesion and graft model offers several interesting observations regarding the general consequences of neocortical degeneration and the neocortical cellular and neurochemical interactions of a neurotrophic nature; however, studies that are more detailed are needed.

Immunological aspects of neural grafting in the mammalian central nervous system.

Abstract: Publisher Summary This chapter discusses the immunological aspects of neural grafting in the mammalian central nervous system. The central nervous system (CNS) tissue, under normal conditions, seems to express low levels of MHC antigens; however, the available data indicate that they may be expressed under certain circumstances. This chapter describes various immunological aspects of neural grafting in the mammalian central nervous system. There seems to be no correlation between macromolecular leakage across the blood-brain barrier (BBB) and xenograft rejection, as a later rejection can occur after withdrawal of immunosuppression, when BBB function is restored. Although, a BBB may be formed in neural grafts, the origin of vessels, the expression of donor type major histocompatibility complex (MHC) structures on the vessels and the presence of homing structures for lymphocytes on the vessels in the graft area are likely to be relevant factors for graft rejection. Intracerebral neural xenografts generally fail unless the hosts are immunosuppressed, whereas the present allografts survive in all of the grafted mice, for up to six to seven weeks, without immunosuppression. The long-term allograft survival under these conditions is difficult to explain, and clearly requires further investigation.

Striatal grafts in the ibotenic acid-lesioned neostriatum: functional studies.

Abstract: Publisher Summary Studies with striatal tissue grafted into the denervated neostriatum suggest that functional recovery in this model system may be attributable to the graft tissue providing at least partial reconstruction of both afferent and efferent components of a damaged circuitry. This chapter provides an overview of the consequences of pharmacological manipulation of host dopamine systems on the behavior of, and neurotransmitter turnover in, rats with lesions and striatal grafts. Transplantation of striatal tissues to the denervated neostriatum of rats has provided a powerful model system for the study of the functional incorporation of embryonic neural grafts into the neural circuitry of the adult mammalian brain. The recovery from behavioral deficits induced by the lesions in grafted animals suggests that the grafted cells can provide at least partial reconstruction of damaged neural systems. However, the extent to which the functional connections or the internal organizations of the grafts are either normal or complete remains to be determined.

Can human fetal dopamine neuron grafts provide a therapy for Parkinson's disease?

Abstract: Publisher Summary The motor symptoms in patients with Parkinson's disease (PD) are considered to be because of severe dopamine (DA) depletion in forebrain striatal areas This chapter discusses and summarizes the data obtained so far on the morphological, functional, and immunological characteristics of grafted human fetal dopamine (DA) neurons The experimental data obtained by grafting human fetal DA neurons to rats clearly suggest that these cells could provide an excellent source of donor tissue for transplantation in PD patients Human fetal DA neurons survive intracerebral transplantation, reinnervate the DA-depleted striatum, and form synaptic contacts with host striatal neurons The estimation of the survival and growth capacity of grafted DA neurons seem to indicate that implantation of a limited amount of human fetal mesencephalic tissue could markedly restore DA neurotransmission in a significant portion of the human striatum, sufficient to produce a therapeutically valuable improvement of motor performance in a patient with PD However, the potential medical risks of intracerebral neural grafting need to be considered very carefully and weighed against the potential benefit of an improved motor function for the patient, when embarking upon clinical trials

Chapter 10 Intracerebral grafting of fetal noradrenergic locus coeruleus neurons: evidence for seizure suppression in the kindling model of epilepsy

Abstract: Publisher Summary Kindling is one of the most extensively studied animal models of epilepsy, whereby repeated administration of an initially subconvulsive electrical stimulus results in progressive intensification of stimulus-induced seizure activity. This chapter discusses the : (1) current knowledge on the role of the locus coeruleus (LC) system in kindling epilepsy; (2) describe morphological and functional characteristics of grafted fetal LC neurons; and (3) discuss the data presented in the chapter to indicate that such grafts can retard the development of seizures in kindling epilepsy. Kindling in the noradrenaline (NA)-depleted rat seems to provide a very suitable model for studies on the functional potential of grafted LC neurons. The data presented in the chapter indicates that such neurons can reinstate the seizure-suppressant action normally exerted by the intrinsic LC system. The chapter suggests that grafted neurons can modify the excitability of an epileptic brain region. Intracerebral implantation of inhibitory neurons, such as noradrenergic and GABAergic ones may, therefore, provide a new research strategy to control the generation or spread of seizure activity.

Striatal grafts in the ibotenic acid-lesioned neostriatum: ultrastructural and immunocytochemical studies.

Abstract: Publisher Summary Striatal grafts placed into the ibotenic acid-lesioned neostriatum are able to ameliorate not only lesion induced locomotor hyperactivity, but also complex behaviors, such as T-maze, learning and tasks involving manual dexterity, such as paw reaching for food. This chapter provides an anatomical background to these behavioral and functional graft effects, as assessed by examining the ingrowth of host dopamine (DA) afferents into the striatal graft in the same group of rats used in the paw reaching and γ-aminobutyric acid (GABA) release experiments. The results presented in the chapter confirm that the host DA system is able to innervate the striatal grafts implanted into the ibotenic acid-lesioned neostriatum. The chapter suggests a possible DA-dependent mechanism for the graft-induced recovery in motor behavior and in the restoration of graft-dependent GABA release. The similarity of the established synaptic contacts of this ingrowing DA system to the normal DA striatal innervations may indicate that the host brain is not only able to accept neuronal grafts, but also to integrate them into its functional circuitry.

The Peripheral nervous system

Abstract: I. Development of the peripheral nervous system: cell line segregation and chemical differentation of neural crest cells (N.M. Le Douarin and J. Smith). II. Neurotransmitter plasticity in the peripheral nervous system (I.B. Black, J.E. Alder and E.F. La Gamma). III. Neurotransmitter plasticity and its regulation by environmental factors in vitro and in viro (S.C. Landis). IV. The ultrastructure of noradrenergic and cholinergic neurons in the autonomic nervous system (Ph.R. Gordon-Weeks). V. The ultrastructure of peptide-containing neurons (I.M. Varndell and J.M. Polak). VI. Chemical neuroanatomy and the analysis of neuronal circuitry in the enteric nervous system (J.B. Furness, I.K. Llewellyn-Smith, J.C. Bornstein and M. Costa). VII. Peptide hormone-producing endocrine/paracrine cells in the gastroentero-pancreatic region (F. Sundler and R. Hakanson). VIII. Transmitters and peptides in autonomic ganglia (M. Schultzberg and B. Lindh). IX. Autonomic innervation of the cardiovascular system (Chr. Owman). X. Airways, oral cavity and salivary glands: classical transmitters and peptides in sensory and autonomic motor neurons (J.M. Lundberg, C.-R. Martling and T. Hokfelt). XI. Origin, distribution, and functional aspects of aminergic and peptidergic nerves in the male and female reproductive tracts (Chr. Owman and M. Stjernquist). XII. The innervation apparatus of the rodent iris (L. Olson, Chr. Ayer-le Lievre, H. Bjorklund, T. Ebendal, K.-O, Hedlung, T. Hokfelt, T. Melander, A. Seiger and I. Stromberg). XIII. The sensory system (C.J. Dalsgaard). XIV. Transmitter substances in the peripheral nervous system: an overview of the vertebrates (G. Campbell). Subject index.

Restoration and deterioration of function by brain grafts in the septohippocampal system.

Abstract: Publisher Summary Several features make the septohippocampal system useful, especially for the study of physiological mechanisms of graft-host interactions, such as the hippocampus possesses electrical rhythms, which vary with ongoing behavior in a specific manner, and the excitability changes within the hippocampus are easy to monitor. This chapter discusses the possible mechanisms of electrophysiological recovery in the damaged septohippocampal system following transplantation of solid pieces or suspensions of fetal brain tissue into the lesion cavity or into the hippocampus, and the epileptogenic properties of hippocampal grafts. The experiments, using the septohippocampal model to study the mechanisms of action of brain grafts, suggest that a likely mechanism of restoration of physiological activity of the deafferented hippocampus is a passive bridging action of the graft between the host septum and hippocampus. The chapter demonstrates the reciprocal physiological and anatomical connections between the graft and host, and shows that hippocampal grafts can serve as an implanted epileptic focus, which may further worsen the function of the already damaged brain. However, experiments are required that determine why under certain conditions the grafts produce epileptic activity, while under seemingly similar conditions they lead to the restoration of physiological function of damaged brain circuitries.

Chapter 7 Studies on host afferent inputs to fetal striatal transplants in the excitotoxically lesioned striatum

Abstract: Publisher Summary The grafts of fetal striatal tissue can effectively ameliorate the behavioral impairments in both conditioned and unconditioned behaviors that result from striatal lesions induced with excitotoxic amino acids. This chapter describes and aims to investigate the extent of the possible ingrowth from the host brain into the striatal transplants in the excitotoxically lesioned striatum. The results suggest that fetal striatal grafts in the ibotenic acid-lesioned striatum receive afferent host brain inputs from the substantia nigra (SN), the thalamus and to some extent also from the amygdala, entorhinal cortex and the dorsal raphe nuclei. The functional importance of the various putative host brain afferents is yet largely unknown. However, it has been shown that the dopaminergic afferents form abundant synaptic contacts with neurons within the striatal grafts, and pharmacological evidence is available showing that striatal graft function is under the functional regulation of the afferent dopaminergic input. The combined anatomical and behavioral data indicate that the intrastriatal grafts become anatomically and functionally integrated with the host brain.

Intracerebral transplantation of dopamine neurons: understanding the functional role of the mesolimbocortical dopamine system and developing a therapy for Parkinson's disease.

Abstract: The first reports of successful neural grafting to the mammalian brain originate from the turn of the century.' However, the field never gained much attention until the 1970s when the first reports appeared showing that grafted neurons could affect the behavior of the recipient mammal and reduce the neurological symptoms induced by a prior lesion of the host b ~ a i n . ~ , ~ These findings stimulated an almost explosive interest in the field of neural grafting and led to the engagement of several diverse disciplines of the neurosciences that have, using a multidisciplinary approach, contributed to ad increased understanding of the capacity and limitations of grafted neurons. In many respects, experiments involving grafts of fetal dopamine (DA) neurons have come to

Chapter 22 Noradrenaline-containing transplants in the adult spinal cord of mammals

Abstract: Publisher Summary The spinal cord of the adult rats is a suitable environment for the survival of transplants of embryonic noradrenaline (NA) neurons transplanted either as solid pieces or as cell suspensions This chapter provides an overview of the growth and survival, neurotransmitter expression and turnover, and function of these NA transplants in the adult mammalian spinal cord The NA containing neurons in the brain stem are ideally suited for these studies because they (1) have measurable functions in the cord, (2) can be selectively lesioned with a neurotoxin, 6-hydroxydopamine (6-OHDA), and (3) can be localized quantitatively with both morphological and biochemical methods The most likely type of regeneration that can be achieved clinically is the reconstruction of intersegmental circuits Transplants of adrenal medulla layered upon the surface of the cord within the subarachnoid space induce analgesia in rats The chapter shows that transplantation methods have potential for studying the degeneration and regeneration of the spinal cord and, most importantly, they have potential for the reconstruction of the injured spinal cord

Trophic effects on cholinergic striatal interneurons by submaxillary gland transplants.

Abstract: Publisher Summary This chapter describes and investigates whether intracerebrally grafted mouse or rat submaxillary glands, which are known to be rich sources of nerve growth factor (NGF) production, are able to survive and capable of exerting an NGF-like trophic effect on forebrain cholinergic neurons in adult rats. The chapter shows that intracerebrally grafted pieces of submaxillary gland from the adult male mice are able to survive grafting for at least two weeks in the brains of immunosuppressed adult male rats, although the survival rate is low. A higher survival rate is seen with mouse submaxillary glands from neonatal donors, which is left to mature over four weeks following grafting. The results presented in this chapter suggest that the submaxillary gland grafts exert a trophic effect on the cholinergic interneurons in the striatum of adult rats. Because the effect is seen with grafts of male mouse submaxillary glands, but not with the NGF-poor rat glands, the chapter proposes that the graft-induced trophic response is mediated through the release of NGF into the host striatal tissue or the cerebrospinal fluid.

Physiology of graft-host interactions in the rat hippocampus.

Abstract: Publisher Summary The transplanted tissue can promote local processes of regeneration, prevent retrograde degeneration, or simply serve as a slow-release biological capsule, which discharges the appropriate neurotransmitter in a random fashion into the intercellular space. This chapter describes the physiology of graft-host interactions in the rat hippocampus. The chapter also addresses two main questions that guide the research on the physiology of graft-host interactions, (1) can the graft substitute for the damaged host tissue, be incorporated into host circuits and function as expected of a normal host tissue; and (2) can the graft serve as a simple model system for asking questions relevant to normal brain operation. Independent of the possible restoration of functions, the graft can be used as a simple model for complex networks in the brain. The chapter indicates that given the existing limitation of resolution of electrophysiological techniques in the in vitro slice preparation, the heterogeneity of grafted tissue and synapse formation with selective populations of host neurons, the graft should be useful for examining basic questions relevant to central neurotransmission.

Release of acetylcholine and its dopaminergic control in slices from striatal grafts in the ibotenic acid-lesioned rat striatum.

Abstract: Tritium accumulation during incubation with 3-H-choline, and the efflux as well as the electrically evoked overflow of tritium during subsequent superfusion, were investigated in slices from unilateral striatal suspension grafts 16 to 20 weeks after implantation into the previously ibotenic acid-lesioned rat striatum Slices from non-operated animals, from striata contralateral to grafts, and from animals with acute ibotenic acid lesions of the striatum were studied in parallel The accumulation of tritium and the overflow of tritium in response to electrical stimulation (2 min, 3 Hz) were markedly impaired in acutely lesioned striata In graft slices, tritium accumulation and the subsequent electrically evoked overflow were greater than in slices obtained after acute lesions, but were still smaller than in non-operated animals or in the contralateral striata The dopamine D2-receptor agonist quinpirole inhibited the electrically evoked overflow of tritium in grafts, but only to a small extent The D2-receptor antagonist sulpiride increased, whereas the dopamine uptake inhibitor nomifensine and the dopamine releasing drug amphetamine decreased the evoked overflow in slices from non-operated rats and from striata contralateral to grafts, but had no significant effect in grafts As in graft slices, the release of acetylcholine in striata from animals in which the mesostriatal dopamine pathway had been lesioned by 6-hydroxy-dopamine was not changed by sulpiride and amphetamine, and was only minimally decreased by nomifensine Our data show that striato-striatal grafts can partly restore the impaired choline accumulation and acetylcholine release in excitotoxinlesioned striata Functional D2-receptors are present on graft cholinergic cells, but are not activated by endogenous dopamine under the present in vitro conditions