Showing papers by "Anders Björklund published in 1996"

Short-Term GDNF Treatment Provides Long-Term Rescue of Lesioned Nigral Dopaminergic Neurons in a Rat Model of Parkinson’s Disease

Abstract: Glial cell line-derived neurotrophic factor (GDNF) has been shown to exert neuroprotective effects on dopamine (DA) neurons in vivo. Here we report long-term rescue of nigral DA neurons after delayed short-term GDNF administration in a rat lesion model that reproduces the slowly progressing degenerative process seen in Parkinson's disease. GDNF injected close to the substantia nigra provided near-complete protection and persistent survival of the lesioned nigral neurons for at least 4 months after discontinuation of GDNF treatment. Long-term rescue of the nigral cells, however, was not accompanied by any significant reinnervation of the lesioned striatal target or any signs of functional recovery in either drug-induced or spontaneous motor behaviors. We conclude that not only preservation of the nigral DA neurons but also restoration of striatal DA function is necessary for functional recovery in the rat Parkinson model.

Protection of the Neostriatum against Excitotoxic Damage by Neurotrophin-Producing, Genetically Modified Neural Stem Cells

Abstract: Huntington's disease is a progressive neurodegenerative disease that affects the striatum, above all, the GABAergic striatal projection neurons. In the present study, we have explored the use of genetically modified neural stem cell lines producing nerve growth factor (NGF) or brain-derived neurotrophic factor (BDNF) as a means to protect the striatal neurons against excitotoxic damage after transplantation to the striatum, 1 week before the injection of quinolinic acid into the same area. One month after the lesion, striatal degeneration, lesion size, and loss of DARPP-32-positive projection neurons were only slightly affected by the BDNF-secreting cells, but substantially prevented when NGF-producing stem cells were used as a source of exogenous trophic factor; innervation of the target fields (pars reticulata of the substantia nigra and the globus pallidus) was preserved as well. Cholinergic striatal interneurons (choline acetyltransferase- immunoreactive) were affected by the lesion and completely rescued by the NGF-transduced cells. The astroglial and microglial reactions to the excitotoxic lesion were substantially reduced in the striata, which had received transplants of NGF-producing cells. The generalized protective effects of the NGF-producing cell grafts in this model are discussed in the context of an indirect action preventing the development of toxicity mediated by cellular elements in the host striatum in response to the excitotoxin. We conclude that continuous supply of trophic factors by means of genetically modified neural stem cells represents a highly effective procedure to counteract neuronal degeneration in the excitotoxically lesioned striatum.

Long-term functional recovery from age-induced spatial memory impairments by nerve growth factor gene transfer to the rat basal forebrain

Abstract: Nerve growth factor (NGF) stimulates functional recovery from cognitive impairments associated with aging, either when administered as a purified protein or by means of gene transfer to the basal forebrain. Because gene transfer procedures need to be tested in long-term experimental paradigms to assess their in vivo efficiency, we have used ex vivo experimental gene therapy to provide local delivery of NGF to the aged rat brain over a period of 2.5 months by transplanting immortalized central nervous system-derived neural stem cells genetically engineered to secrete NGF. By grafting them at two independent locations in the basal forebrain, medial septum and nucleus basalis magnocellularis, we show that functional recovery as assessed in the Morris water maze can be achieved by neurotrophic stimulation of any of these cholinergic cell groups. Moreover, the cholinergic neurons in the grafted regions showed a hypertrophic response resulting in a reversal of the age-associated atrophy seen in the learning-impaired aged control rats. Long-term expression of the transgene lead to an increased NGF tissue content (as determined by NGF-ELISA) in the transplanted regions up to at least 10 weeks after grafting. We conclude that the gene transfer procedure used here is efficient to provide the brain with a long-lasting local supply of exogenous NGF, induces long-term functional recovery of cognitive functions, and that independent trophic stimulation of the medial septum or nucleus basalis magnocellularis has similar consequences at the behavioral level.

Selective Immunolesioning of the Basal Forebrain Cholinergic System Disrupts Short‐term Memory in Rats

Abstract: Selective depletion of nerve growth factor receptor-bearing neurons in the basal forebrain cholinergic system nuclei by the immunotoxin 192 IgG-saporin offers a new and highly useful tool for the study of the role of the forebrain cholinergic system in cognitive functions. In the present study, we have tested the effects of 192 IpG-saporin in an operant delayed matching-to-position task which has previously been used to discriminate between delay-dependent learning impairments and delay-independent disturbances of non-mnemonic processes. Rats were first trained to criterion performance and then received intraventricular injections of 5 microg of 192 IgG-saporin 4 weeks prior to a second testing session. Rats with 192 IgG-saporin lesions displayed a significant delay-dependent decline in performance compared to normal controls, indicating a deficit in short-term memory. Administration of the muscarinic blocker scopolamine (0.5 mg/kg, i.p.) produced more pronounced impairment in the performance of the normal control rats across all delays, and induced further impairment also in animals with 192 IgG-saporin lesions. These effects were not observed following control injections of methyl scopolamine, suggesting that the impairment induced by scopolamine was due to the blockade of central muscarinic receptors. No improvement in performance was observed in either group following systemic treatment with the muscarinic cholinergic agonist arecoline (1.00 mg/kg). Biochemical and morphological analyses confirmed the selective and severe (>90-95%) depletion of cholinergic neurons throughout the septal-diagonal band area and the nucleus basalis region by the intraventricular 192 IgG-saporin treatment. Although the immunotoxin was observed to produce additional damage to the cerebellar Purkinje cells, no gross motor abnormalities were observed that could contribute to the effects on accuracy in the task used here. In conclusion, the results show that selective combined lesions of the basal forebrain cholinergic neurons in the septal-diagonal band area and nucleus basalis produce long-lasting impairments in short-term memory, thus providing further support for a role of this system in cognitive functions.

Ex Vivo Gene Transfer of Brain‐derived Neurotrophic Factor to the Intact Rat Forebrain: Neurotrophic Effects on Cholinergic Neurons

Abstract: Neurotrophic effects of human brain-derived neurotrophic factor (hBDNF) on forebrain cholinergic neurons were addressed after ex vivo gene transfer to the intact adult rat brain, using a conditionally immortalized neural progenitor cell line (CINP) engineered to secrete the neurotrophin (2.8 ng/h/10(6) cells). This cell line was derived by repeated retroviral infection of the parental neural precursor line HiB5 followed by subcloning. The cells survived well in the host brain for long periods of time (up to 4 weeks), and induced a hypertrophic response of cholinergic neurons (positive for acetylcholinesterase, choline acetyltransferase or low-affinity nerve growth factor receptor) in the nucleus basalis magnocellularis and striatum. We conclude that these cholinergic cell groups are responsive to a low-level supply (nanograms per day) of BDNF in vivo when the neurotrophin is administered locally in the vicinity of the cell bodies.

Host regulation of glial markers in intrastriatal grafts of conditionally immortalized neural stem cell lines.

Abstract: After transplantation into the adult CNS the immortalized neural stem cell lines ST14A and HiB5 differentiate preferentially into glia-like cells. After lesions of the host brain, which activate resting glial populations, the grafted cells responded with up-regulation of glial markers and a change in morphology towards a reactive state. The protein expression followed the same pattern as in the host glial population. The results show that the astrocytes formed by the grafted neural stem cells become functionally integrated in the host brain and that they may take an active part in the reactive gliosis caused by brain damage.

Extensive reinnervation of the hippocampus by embryonic basal forebrain cholinergic neurons grafted into the septum of neonatal rats with selective cholinergic lesions.

Abstract: Reconstruction of the septohippocampal pathways by axons extending from embryonic cholinergic neuroblasts grafted into the neuron-depleted septum has been explored in the neonatal rat by using a novel lesioning and grafting protocol. Neonatal ablation of the basal forebrain cholinergic projection neurons, accompanied by extensive bilateral cholinergic denervation of the hippocampus and neocortex, was produced at postnatal day (PD) 4 by 192 immunoglobulin (IgG)-saporin intraventricularly. Four days later, cholinergic neuroblasts (from embryonic day 14 rats) were implanted bilaterally into the neuron-depleted septum by using a microtransplantation approach. The results show that homotopically implanted septal neurons survive and integrate well into the developing septal area, extending axons caudally along the myelinated fimbria-fornix and supracallosal pathways that are able to reach the appropriate targets in the denervated hippocampus and cingulate cortex as early as 4 weeks postgrafting. Moreover, the laminar innervation patterns established by the graft-derived axons closely resembled the normal ones and remained essentially unchanged up to at least 6 months, which was the longest postoperative time studied. The reinnervating fibers restored tissue choline acetyltransferase activity (up to 50% of normal) in the dorsal hippocampus and the parietooccipital cortex. Retrograde labeling with Fluoro-Gold from the host hippocampus combined with immunocytochemistry confirmed that most of the projecting neurons, indeed, were cholinergic. The results suggest that the graft-host interactions that are necessary for target-directed axon growth are present in the septohippocampal system during early postnatal maturation. Thus, the present approach may contribute to overcome the functional limitations inherent in the use of ectopically placed intrahippocampal transplants.

Income Inequality and Income Mobility in the Scandinavian Countries Compared to the United States

Abstract: This paper compares income inequality and income mobility in the Scandinavian countries and the United States during the 1980's. The results demonstrate that inequality is greater in the United States than in the Scandinavian countries and that the ranking of countries with respect to inequality remains unchanged when the accounting period of income is extended from one to 11 years. The pattern of mobility turns out to be remarkably similar despite major differences in labor market and social policies between the Scandinavian countries and the United States.

Cerebellum, basal ganglia, olfactory system

Abstract: The Cerebellum, Chemoarchitecture and Anatomy (J. Voogd, D. Jaarsma, E. Marani). 1. Introduction. 2. Cytology of the cerebellar cortex. 3. Chemical anatomy of the cerebellar cortex. 4. Gross anatomy of the mammalian cerebellum. 5. The cerebellar nuclei. 6. Efferent and afferent connections of the cerebellar cortex: corticonuclear, olivocerebellar and mossy fiber connections and cytochemical maps. 7. Postscript. 8. Acknowledgements. 9. References. II. The Basal Ganglia (C.R. Gerfen, C.J. Wilson). 1. Introduction. 2. Organizational overview. 3. Cerebral cortex input to striatum. 4. Striatum. 5. Globus pallidus (external segment). 6. Subthalamic nucleus. 7. Substantia nigra/entopeduncular nucleus. 8. Connectional organization of basal ganglia. 9. Relationship between cortex and basal ganglia. 10. Striatal patch/matrix compartments. 11. Direct/indirect striatal output system. 12. Acknowledgements. 13. References. III. The Olfactory System (M.T. Shipley, J.H. McLean, L.A. Zimmer, M. Ennis). 1. Introduction. 2. The main olfactory bulb. 3. Primary olfactory cortex. 4. Integration of the main olfactory system with other functions. 5. The accessory olfactory system. 6. "Non-olfactory" modulatory inputs to the olfactory system. 7. Acknowledgements. 8. Abbreviations. 9. References. Subject Index.

Cell transplantation and gene therapy in Parkinson disease

Abstract: In 1995 the Anders Jahre Prize for medical research was shared by Professor Lars Olson, Stockholm (Nord Med 1/96), and Professor Anders Bjorklund, Lund. Using newly developed methods, Anders Bjorklund has mapped important parts of the central nervous system and neurotransmitters in the brain. Bjorklund and co-workers have therapeutically transplanted neurones to parts of the brain that, owing to disease or injury, are deficient in essential neurotransmitters. During recent years, the transplantation of fetal nerve cells has been introduced as a possible new therapeutic procedure in Parkinson's disease. Although promising results have been obtained in clinical trials both in Europe and North America, the technique needs further improvement to enhance cell survival, effectiveness and reproducibility. Moreover, an essential long-term goal is to eliminate dependence on a continuous supply of fetal tissue, which is both ethically and practically problematic. Current research is focused on ways to promote the survival and growth of grafted cells, and on the use of gene transfer procedures to generate alternative dopamine-producing of trophic factor-producing cells.