Showing papers by "Anders Björklund published in 1992"
TL;DR: Bilateral implantation of fetal mesencephalic tissue can induce substantial long-term functional improvement in patients with parkinsonism and severe dopamine depletion and is accompanied by increased uptake of fluorodopa by the striatum.
Abstract: Background. Intracerebral transplantation of fetal dopaminergic neurons is a promising new approach for the treatment of Parkinson's disease. Patients with parkinsonism induced by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) have a relatively stable lesion limited to the nigrostriatal system, rendering them ideal candidates for transplantation. Improvement of motor function after neural grafting has previously been observed in nonhuman primates with MPTP-induced parkinsonism. Methods. We grafted human fetal tissue from the ventral mesencephalon (obtained six to eight weeks after conception) bilaterally to the caudate and putamen in two immunosuppressed patients with severe MPTP-induced parkinsonism, using a stereotaxic technique. The patients were assessed regularly with clinical rating scales, timed tests of motor performance, and [18F]fluorodopa positron-emission tomography during the 18 months before the operation and the 22 to 24 months after the operation. Results. Both patients had s...
512 citations
TL;DR: The results indicate that degenerative and/or atrophic changes in the forebrain cholinergic system and decline in spatial learning ability are parallel processes during aging.
292 citations
TL;DR: The results show that the forebrain DA and NA projections to cortical and striatal targets are differentially regulated during ongoing behavior, that the mesocortical and mesostriatal DA systems respond quite differently to stressful and rewarding stimuli; and that the NA projection to MFC is more responsive to stressfuland rewarding stimuli than the ones innervating the striatum.
241 citations
TL;DR: It is reported that an intracerebroventricular injection of this 192 IgG-saporin conjugate induces a severe, long-lasting spatial learning impairment, as assessed in the Morris water-maze task.
Abstract: A monoclonal antibody to the low-affinity NGF receptor, 192 IgG, coupled to a cytotoxin, saporin, was recently introduced as an efficient selective neurotoxin for the NGFr-bearing cholinergic neurones in the rat basal forebrain. In the present study we report that an intracerebroventricular injection of this 192 IgG-saporin conjugate induces a severe, long-lasting spatial learning impairment, as assessed in the Morris water-maze task. This behavioural impairment was associated with 65-90% depletion of choline acetyltransferase activity (ChAT) in the hippocampus and cortex. ChAT activity associated with other cholinergic neurone systems in the brain (striatum, mesencephalon, spinal cord), was left virtually unaffected. This new immunotoxin holds great promise as a tool for selective and efficient lesions of the forebrain cholinergic system in functional and behavioural studies.
207 citations
TL;DR: The kinetic data provide evidence of disease progression in the unoperated striatum, which balanced against increasing graft function, may explain why clinical improvement reached a plateau within months after surgery.
Abstract: Two patients with Parkinson's disease who underwent implantation of fetal mesencephalic tissue into the putamen were serially studied using positron emission tomography and [18F]6-L-fluorodopa ([18F]dopa). The uptake of [18F]dopa is related to the functional integrity of the presynaptic dopaminergic system. Preoperative studies revealed a marked decrease in putamen [18F]dopa uptake, with lesser involvement of the caudate. Two and 4 months, respectively, after operation, both patients demonstrated functional improvement, as described elsewhere. One patient was scanned 5, 8, and 13 months after the operation and the other was scanned 7 and 12 months after the operation. In both patients, [18F]dopa uptake increased within the operated putamen despite a progressive decrease in tracer uptake in the unoperated striatal structures. We believe that this increased uptake of [18F]dopa at the implantation site represents functional integrity within a surviving neural graft. While there has been little further clinical improvement beyond the fifth postoperative month, the uptake of [18F]dopa at the operation site in both patients has progressively increased. The kinetic data provide evidence of disease progression in the unoperated striatum, which, balanced against increasing graft function, may explain why clinical improvement reached a plateau within months after surgery.
201 citations
TL;DR: Tyrosine hydroxylase (TH) immunohistochemistry revealed that the vast majority of the rostrally projecting HNF‐positive axons were also TH‐ positive, and that the graft‐derived axons gave rise to dense TH‐positive terminal networks, above all in large areas of the previously denervated caudate putamen.
Abstract: Dissociated ventral mesencephalon of 6 to 8-week-old human embryos were implanted by stereotaxic injection at different sites along the nigrostriatal pathway in adult rats, previously subjected to a 6-hydroxydopamine lesion of the intrinsic mesotelencephalic dopamine pathways. The recipients were immunosuppressed by daily injections of cyclosporin A to prevent rejection. At 13-20 weeks after transplantation, the implanted human neurons and their associated fiber outgrowths were visualized with a species-specific antibody recognizing human, but not rat, intermediary neurofilaments (HNF). From implants placed in the host rostral mesencephalic region, HNF-positive axonal projections were seen to extend in large numbers rostrally along the medial forebrain bundle and the internal capsule, and ramify within the caudate putamen, the ventral striatum and the amygdaloid nuclei (a distance of about 5-6 mm), and more sparsely in the frontal cortex and the olfactory bulb (a distance of about 10 mm). From implants placed in the internal capsule, abundant HNF-positive axons extended in the rostral, but not caudal, direction along the myelinated fiber bundles into the caudate putamen and the ventral striatum. Tyrosine hydroxylase (TH) immunohistochemistry revealed that the vast majority of the rostrally projecting HNF-positive axons were also TH-positive, and that the graft-derived axons gave rise to dense TH-positive terminal networks, above all in large areas of the previously denervated caudate putamen. From control implants of cortical neuroblasts, axonal projections were seen along the medial forebrain bundle and the internal capsule, but the axons were TH-negative and showed only sparse projections to the striatal areas. Instead, dense projections were seen, e.g., in the frontal cortex. The results demonstrate a remarkable ability of human mesencephalic neuroblasts to extend axons along the trajectories of the nigrostriatal and mesolimbocortical pathways to reach and innervate the principal striatal and limbic target areas in the forebrain. This shows that the basic requirements for the formation of long axonal pathways may be present in the adult mammalian central nervous system (CNS) at least for certain types of projection neurons. Furthermore, it implies that the developing human neuroblasts can escape the inhibitory features known to be present along myelinated growth trajectories in the adult mammalian brain. In addition, the present approach may offer new possibilities for functional neural grafting in the rat Parkinson model, since transplanted nigral neurons placed in their natural position within the rostral mesencephalon could provide an anatomically and functionally more integrated system than the standard model with ectopically placed intrastriatal nigral grafts.
198 citations
TL;DR: The results provide evidence that behaviorally functional grafts restore dopaminergic neurotransmission and normalize dopamine receptor function in the denervated striatum, and that these effects are likely to depend on both synaptic and extrasynaptic mechanisms.
143 citations
Book•
01 Jan 1992
TL;DR: Staging and dissection of rat embryos, S.D. Lund and R.B. Dunnett grafting genetically modified cells within the rat CNS, and the use of peripheral nerve grafts to study CNS regeneration.
Abstract: Staging and dissection of rat embryos, S.B. Dunnett grafting genetically modified cells within the rat CNS, M.D. Kawaja et al neural transplantation in adult rats, A. Bjorklund and S.B. Dunnett intracerebral transplantation to immature hosts, R.D. Lund and K.T. Yee the use of peripheral nerve grafts to study CNS regeneration, M. Vidal-Sanz et al transplantation of glial cells into areas of demyelination in the adult rat spinal cord, W.F. Blakemore and A.J. Crang neural transplantation in primates, L.E. Annett and R.M. Ridley dissection, preparation and implantation of human embryonic brain tissue, P. Brundin immonological considerations in neural transplantation, R.D. Lund and R. Bannerjee identifying grafted cells, J, Cadusseau and M. Peschanski.
121 citations
TL;DR: The present findings are consistent with the idea that striatal c‐fos induction by dopaminergic agents is primarily mediated by an interaction with D1 ‐receptors, which are thought to be selectively localized on neurons projecting to SN.
Abstract: Fluorogold or rhodamine-labelled latex beads were injected in the substantia nigra (SN) or the globus pallidus (GP) in order retrogradely to label striatal output neurons that project to the two target structures. Ten days later, striatal c-fos was induced by systemic administration of cocaine (five normal rats; 25 mg/kg cocaine i.p. 2 h before killing) or apomorphine (five unilaterally dopamine-denervated rats; 0.25 mg/kg apomorphine s. c. 2 h before killing), and detection of the Fos protein in the striatum was achieved by immunofluorescence. Sections through the caudate-putamen that displayed good labelling from both SN and GP were selected for a quantitative analysis: the number of retrogradely labelled cells that exhibited Fos immunoreactivity, as well as the total number of retrogradely labelled cells located within a grid (0.16 mm2 in size) were counted manually at 25 x magnification. Cocaine induced a proportionally higher c-fos expression in striato-nigral compared to striato-pallidal neurons, whereas apomorphine activated Fos almost exclusively in striato-nigral neurons. The present findings are consistent with the idea that striatal c-fos induction by dopaminergic agents is primarily mediated by an interaction with D1-receptors, which are thought to be selectively localized on neurons projecting to SN.
120 citations
TL;DR: Findings indicate that fetal ventral mesencephalic transplants normalize dopamine receptor-mediated function in the 6-hydroxydopamine-lesioned caudate-putamen and nucleus accumbens, as well as in a primary target of the striatal output neurons, the globus pallidus.
103 citations
TL;DR: The results show that surgical or pharmacological manipulations of the ascending brainstem monoaminergic systems, which innervate wide areas of the forebrain, including the septum and the hippocampal formation, have pronounced effects on septo-hippocampal cholinergic activity.
TL;DR: The results show that grafted cholinergic neurons can be functionally integrated into the host brain, allowing the grafted neurons to be activated in the correct behavioural contexts, although the changes in acetylcholine overflow were overall smaller and more variable than normal.
TL;DR: Adult rats with acute partial lesions of their upper thoracic spinal cords were implanted bilaterally with cell suspensions of 6-7 week-old embryonic human spinal cord tissue one segment above or below the lesions, and extensive efferent projections were demonstrated extending longitudinally from the grafts into the host spinal cord.
Abstract: Adult rats with acute partial lesions of their upper thoracic spinal cords were implanted bilaterally with cell suspensions of 6-7 week-old embryonic human spinal cord tissue one segment above or below the lesions. After 14-19 weeks, the animals were perfusion-fixed and the tissue analysed with a light microscope after immunocytochemical labelling with an antiserum recognizing human, but not rat, intermediary neurofilaments. Using this method, extensive efferent projections were demonstrated extending longitudinally from the grafts into the host spinal cord, both in the caudal and rostral directions. Within the white matter tracts, dense bundles of fibres extended for about 3-4 mm, and single fibres were identified up to 10 mm away from the implants. Axonal growth of this length within host white matter has not previously been observed from intraspinal grafts of rat CNS tissue.
Book•
01 Jan 1992
TL;DR: The development of the serotonergic system in the rat and chick embryo and the ontogeny of neurotransmitters and neuromodulators in the central nervous system are studied.
Abstract: I. The early stages of nervous system development: neurogenesis and neuronal migration (J. Altman). II. Development of central cholinergic neurons (K. Semba). III. Development of dopamine-containing systems in the CNS (A. Kalsbeek, P. Voorn and R.M. Buijs). IV. Immunocytochemical distribution of aromatic l-amino acid decarboxylase (AADC) in rat embryos (C.B. Jaeger and G. Teitelman). V. Phenylethanolamine n-methyltransferase - the adrenaline-synthesizing enzyme (G.A. Foster). VI. Ontogeny of histamine- immunoreactive neurons in the CNS (P. Panula, A. Kinnunen, M.S. Airaksinen, M. Ahonen, O. Happola and E. Castren). VII. Postnatal changes of glutaminase-like immunoreactivity in the olfactory bulb, thalamus, cerebral cortex and cerebellum of the rat (T. Kaneko and N. Mizuno). VIII. Development of neuronal elements with substance p-like immunoreactivity in the central nervous system (M. Sakanaka). IX. Ontogenetic and differential expression of the preproenkephalin and preprodynorphin genes in the rat brain (Y. Morita). X. Ontogeny of pro-opiomelanocortin (POMC)-derived peptides in the brain and pituitary (Y.-Q. Wang, J.-S. Li, H.-M. Li and M. Tohyama). XI. Ontogeny of calcitonin gene-related peptide (CGRP) (S. Inagaki). XII. Ontogeny of the central somatostatinergic system (S. Shiosaka). XIII. Ontogeny of neurotensin immunoreactivity and MRNA in the rat central nervous system (H. Kiyama, M. Sato and P.C. Emson). XIV. Ontogeny of cholecystokinin in the central nervous system (H.-J. Cho and K. Joo). XV. Vasoactive intestinal polypeptide and peptide histidine isoleucine (K. Hares and G.A. Foster). XVI. Development of corticotropin-releasing factor in rat brain (S. Daikoku and S. Hisano). XVII. Neuropeptide Y (G.A. Foster and P.L. Woodhams). XVIII. The development of vasopressin and oxytocin systems in the brain (R.M. Buijs). XIX. Ontogeny of gonadotropin releasing hormone containing neuronal systems in mammals (L. Jennes and M. Schwanzel-Fukuda). XX. Galanin (A.R. Sizer and G.A. Foster). XXI. The development of the serotonergic system in the rat and chick embryo (J.A. Wallace and J.M. Lauder). XXII. An overview of the ontogeny of neurotransmitters and neuromodulators in the central nervous system (M. Tohyama). Subject index.
TL;DR: The results show that the host nigrostriatal dopamine pathway differentially regulates enkephalin and substance P gene expression within striatal grafts and thereby exerts a tonic functional influence over grafted striatal neurons.
Abstract: The effects of dopamine-specific manipulations on neuropeptide gene expression in intrastriatal grafts of fetal striatal tissue were studied by quantitative in situ hybridization histochemistry, using 35S-labeled oligonucleotide probes. Messenger RNA transcripts for the striatal neuropeptides preproenkephalin (PPE) and preprotachykinin (PPT) were detected in neurons forming discrete patches in the striatal grafts. The relative abundance of PPE and PPT mRNA-expressing neurons within the graft patches (51-54%) was similar to that found in normal caudate-putamen. In specimens with intact dopamine afferents the expression of PPE mRNA in grafted neurons was similar to that found in normal caudate putamen, whereas the hybridization signal for PPT mRNA was 27% higher in the graft neurons than in the normal caudate-putamen. Removal of host dopaminergic afferents by 6-hydroxydopamine lesions of the ipsilateral mesostriatal dopamine pathway increased the hybridization signal for PPE mRNA both in the grafts (+84%) and in the spared ipsilateral host caudate-putamen (+125%), whereas the PPT signal was reduced by 53% in the grafts and by 51% in the remaining host caudate-putamen. Similarly, chronic treatment of grafted animals with the dopamine receptor antagonist haloperidol (2 mg/kg per day for 10 days) produced a 146% increase in the PPE signal in the grafts and a 175% increase in the intact contralateral caudate-putamen, whereas the signal for PPT mRNA was again decreased by 52% and 51% in the grafts and host caudate-putamen, respectively. These results show that the host nigrostriatal dopamine pathway differentially regulates enkephalin and substance P gene expression within striatal grafts and thereby exerts a tonic functional influence over grafted striatal neurons.
TL;DR: In this article, the authors analyzed how the participation of marned women in Sweden during the 1970s affected the distribution of family income and found an equalizing effect of wives' income in the sense that family income is more equal than husbands' income.
Abstract: This paper analyses how rising labour force participation of marned women in Sweden during the 1970s affected the distribution of family income. We use the squared coefficient of variation and compare the dispersion of family (factor) income with the dispersion of marned men's income We find an equalizing effect of wives' income, in the sense that family income is more equal than husbands' income. Furthermore, the equalizing effect of female income was stronger in 1980 than in 1967, i.e. when female labour force participation had increased markedly. An examination of hours of work and determinants of wage rates suggests that the equalizing effects stem from wage rates rather than from hours of work. This effect holds in spite of very strong positive correlation between husbands' and wives' education.
TL;DR: DA-receptor-mediated expression of the Fos protein is used as a cellular marker for functional dopaminergic host-graft interactions in the striatal grafts to study transplants of fetal striatum and reveals that the activated graft neurons were, at least in part, DARPP-32-positive.
Journal Article•
Book•
01 Jan 1992
TL;DR: Localization of angiotensin receptor binding sites in the rat brain and brain neuropeptide Y receptors: distribution and possible relevance to function are studied.
Abstract: I. Localization of angiotensin receptor binding sites in the rat brain (A.M. Allen, G. Paxinos, K.F. Song and F.A.O. Mendelsohn). II. Localization of atrial natriuretic peptide B and C receptors in rat brain (J.M. Saavedra, S. Zorad and K. Tsutsumi). III. Bombesin/GRP receptors (T.W. Moody, E. Wada and J. Battey). IV. Calcitonin- and calcitonin gene-releated peptide: receptor binding sites in the central nervous system (G. Skofitsch and D.M. Jacobowitz). V. Corticotropin-releasing hormone receptors (E.B. de Souza). VI. Galanin binding sites in the central nervous system (T. Melander, C. Kohler, S. Nilsson, T. Hokfelt. E. Brodin, E. Theodorsson and T. Bartfai). VII. Gonadotropin releasing hormone receptors in rat brain (L. Jennes and P.M. Conn). VIII. Brain neuropeptide Y receptors: distribution and possible relevance to function (R. Quirion and J-C. Martel). IX. Vasopressin and oxytocin receptors in the rat brain (E. Tribollet). X. Somatostatin receptors (S. Krantic, R. Quirion and G. Uhl). XI. Vasoactive intestinal peptide (VIP) receptors (P.J. Magistretti, J-L. Martin, P.R. Hof and J.M. Palacios). Subject index.
Journal Article•
TL;DR: Although, as it has been described earlier, dopamine transmission is necessary for mediation of behavioural functions of the prefrontal system, it does not change quantitatively in the system during specific activity.
Abstract: Dopamine, norepinephrine and DOPAC were measured in two cortical areas (the medial prefrontal and the posterolateral, Te2) and in the anterior and posterior neostriatum in rats which were exposed to three different experiences for three different lengths of time. One group learned delayed alternation and the two others served as controls. Throughout the training period all animals were housed in single cages. There was no significant effect of the kind of experience on any measure, but the length of exposure did affect some values: the amount of non-precursor dopamine was decreased significantly in both neostriatal samples. A significant increase of dopamine turnover and amount of norepinephrine was found in the Te2 area and in the posterior neostriatal sample. The observed changes are attributed to isolation stress. We conclude that although, as it has been described earlier, dopamine transmission is necessary for mediation of behavioural functions of the prefrontal system, it does not change quantitatively in the system during specific activity.