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Dopaminergic innervation of striatal grafts placed into different sites of normal striatum: differences in the tyrosine hydroxylase immunoreactive growth pattern

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Abstract

When patients with Parkinson’s disease initially show symptoms, approximately 80–85% of their dopaminergic nerve fibers in the striatum have degenerated. It is thus of importance to develop strategies to try to rescue the remaining dopaminergic neurons and to stimulate them to induce sprouting. In this study the goal was to examine whether the different subgroups of dopaminergic neurons in the ventral mesencephalon projecting to the basal ganglia have different sprouting capacities when stimulated by the trophic effect of a fetal striatal graft. Lateral ganglionic eminence was implanted into the lateral ventricle, the midportion of dorsal striatum, globus pallidus, or ventral striatum. Solid tissue pieces from 13- to 15-mm fetuses were stereotactically implanted into adult female Sprague-Dawley rats. At postgrafting week 4 the animals were perfused and processed for tyrosine hydroxylase (TH) immunohistochemistry. Transplants placed in the lateral ventricle were TH-negative, except for two cases with TH-positive fibers where the ependymal layer was disrupted, thereby allowing direct contact between the graft and the adjacent host striatum. The transplants placed into dorsal striatum were innervated by small patches of dopaminergic nerve fibers. Areas between the TH-positive patchy structures remained TH-negative. In grafts placed into globus pallidus, both patchy structures and a less dense TH-positive nerve fiber network was noted. The TH-positive growth pattern in transplants placed in ventral striatum was also devided into patchy and widespread growth. Grafts placed in globus pallidus and ventral striatum revealed significantly larger areas of TH-positive innervation compared with that measured in grafts placed in dorsal striatum and the lateral ventricle. In conclusion, it is possible to induce sprouting of TH-immunoreactive nerve fibers from all areas examined. The most potent areas to initiate dopaminergic growth were the globus pallidus and ventral striatum, where both a patchy dense and a widespread, less dense growth was induced. Thus, if using a trophic stimulus to induce sprouting from remaining dopaminergic nerve fibers in Parkinson’s disease, the preferential target to induce sprouting would be ventromedial striatum and growth would be guided toward dorsal striatum owing to the enhanced dopaminergic growth properties in the ventromedial areas.

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References

  • Alexi T, Hefti F (1993) Trophic actions of transforming growth factor alpha on mesencephalic dopaminergic neurons in culture. Neuroscience 55: 903–918

    Article  PubMed  CAS  Google Scholar 

  • Beck KD, Valverde J, Alexi T, Poulsen K, Moffat B, Vandlen RA, Rosenthal A, Hefti F (1995) Mesencephalic dopaminergic neurons protected by GDNF from axotomy-induced degeneration in the adult brain. Nature 373: 339–341

    Article  PubMed  CAS  Google Scholar 

  • Björklund A, Stenevi U (1979) Reconstruction of the nigrostriatal dopamine pathway by intracerebral nigral transplants. Brain Res 177: 555–560

    Article  PubMed  Google Scholar 

  • Björklund L, Strömberg I (1995) Different types of growth pattern from striatal dopaminergic nerve terminals into striatal or cortical grafts: Effects of haloperidol. Soc Neurosci Abstr 133: 14

    Google Scholar 

  • Bohn MD, Kanuicki M (1990) Bilateral recovery of striatal dopamine after unilateral adrenal grafting into the striatum of the 1-methyl-4-(2′-methylphenyl)-1,2,3,6-tetrahydropyridine (2′CH3-MPTP)-treated mouse. J Neurosci Res 25: 281–286

    Article  PubMed  CAS  Google Scholar 

  • Bohn MC, Cupit L, Marciano F, Gash DM (1987) Adrenal medulla grafts enhance recovery of striatal dopaminergic fibers. Science 237: 913–916

    PubMed  CAS  Google Scholar 

  • Brundin P, Isacson O, Gage F, Björklund A (1986) Intrastriatal grafting of dopamine-containing neuronal cell suspensions: effects of mixing with target or non-target cells. Brain Res Dev Brain Res 24: 77–84

    Article  Google Scholar 

  • Campbell K, Wictorin K, Björklund A (1995) Neurotransmitter-related gene expression in intrastriatal striatal transplant. I. Phenotypical characterization of strital and non-striatal graft regions. Neuroscience 64: 17–33

    Article  PubMed  CAS  Google Scholar 

  • Carvey P, Ptak L, Kao L, Klawans H (1989) Striatal homogenates from animals chronically treated with haloperidol stimulate dopamine and GABA uptake in cultures of rostral mesencephalic tegmentum. Clin Neuropharmacol 12: 425–434

    PubMed  CAS  Google Scholar 

  • Choi-Lundberg DL, Bohn MC (1995) Ontogeny and distribution of glial cell line-derived neurotrophic factor (GDNF) mRNA in rat. Brain Res Dev Brain Res 85: 80–88

    Article  PubMed  CAS  Google Scholar 

  • Clarke DJ, Dunnett SB, Isacson O, Sirinathsinghji DJS, Björklund A (1988) Striatal grafts in rats with unilateral neostriatal lesions. I. Ultrastructural evidence of afferent synaptic inputs from the host nigrostriatal pathway. Neuroscience 24: 791–801

    Article  PubMed  CAS  Google Scholar 

  • Collier T, Martin PN (1993) Schwann cells as a source of neurotrophic activity for dopamine neurons. Exp Neurol 124: 129–133

    Article  PubMed  CAS  Google Scholar 

  • Dahlström A, Fuxe K (1964) Evidence for the existence of monoamine-containing neurons in the central nervous system. I. Demonstration of monoamines in the cell bodies of the brain stem neurons. Acta Physiol Scand [Suppl 62] 232: 1–55

    Google Scholar 

  • Date I, Felten SY, Olschowka JA, Felten DA (1990) Limited recovery of striatal dopaminergic fibers by adrenal medullary grafts in MPTP-treated aging mice. Exp Neurol 107: 197–207

    Article  PubMed  CAS  Google Scholar 

  • Deacon TW, Pakzaban P, Isacson O (1994) The lateral ganglionic eminence is the origin of cells committed to striatal phenotypes: neural transplantation and developmental evidence. Brain Res 668: 211–219

    Article  PubMed  Google Scholar 

  • De Beaurepaire R, Freed WJ (1987) Embryonic substantia nigra grafts innervate embryonic striatal co-grafts in preference to mature host striatum. Exp Neurol 95: 448–454

    Article  PubMed  Google Scholar 

  • Deckel AW, Robinson RG, Coyle JT, Sandberg PR (1983) Reversal of long-term locomotor abnormalities in the kainic acid model of Huntington’s disease by day 18 fetal striatal implants. Eur J Pharmacol 93: 287–288

    Article  PubMed  CAS  Google Scholar 

  • Deckel AW, Moran TH, Robinson RG (1986) Behavioral recovery following kainic acid lesions and fetal implants of the striatum occurs independent of dopaminergic mechanisms. Brain Res 363: 383–385

    Article  PubMed  CAS  Google Scholar 

  • Fiandaca MS, Kordower JH, Hansen JT, Jiao SS, Gash DM (1988) Adrenal medullary autografts into the basal ganglia of Cebus monkeys: injury-induced regeneration. Exp Neurol 102: 76–91

    Article  PubMed  CAS  Google Scholar 

  • Freed WJ, Perlow MJ, Karoum F, Seiger Å, Olson L, Hoffer BJ, Wyatt RJ (1980) Restoration of dopaminergic function by grafting fetal rat substantia nigra to the caudate nucleus: longterm behavioral, biochemical, and histochemical studies. Ann Neurol 8: 510–519

    Article  PubMed  CAS  Google Scholar 

  • Gerfen CR, Baimbridge KG, Thibault J (1987a) The neostriatal mosaic. III. Biochemical and developmental dissociation of patch-matrix mesostriatal systems. J Neurosci 7: 3935–3944

    PubMed  CAS  Google Scholar 

  • Gerfen CR, Herkenham M, Thibault J (1987b) The neostriatal mosaic. II. Patch- and matrix-directed mesostriatal dopaminergic and non-dopaminergic systems. J. Neurosci 7: 3915–3034

    PubMed  CAS  Google Scholar 

  • German DC, Manaye K, Smith WK, Woodward DJ, Saper CB (1989) Midbrain dopaminergic cell loss in Parkinson’s disease: computer visualization. Ann Neurol 26: 507–514

    Article  PubMed  CAS  Google Scholar 

  • Giacobini MMJ, Almström S, Funa K, Olson L (1993) Differential effects of PDGF isoforms on dopamine neurons in vivo: −AA enhances formation, −BB supports cell survival. Neuroscience 57: 923–929

    Article  PubMed  CAS  Google Scholar 

  • Graybiel AM (1984) Correspondence between the dopamine islands and striosomes of the mammalian striatum. Neuroscience 13: 1157–1187

    Article  PubMed  CAS  Google Scholar 

  • Graybiel AM, Pickel VM, Joh TH, Reis DJ, Ragsdale CW Jr (1981) Direct demonstration of a correspondence between the dopamine islands and acetylcholinesterase patches in the developing striatum. Proc Natl Acad Sci USA 78: 5871–5875

    Article  PubMed  CAS  Google Scholar 

  • Graybiel AM, Liu F-C, Dunnett SB (1989) Intrastriatal grafts derived from fetal striatal primordia. I. Phenotypy and modular organization. J Neurosci 9: 3250–3271

    PubMed  CAS  Google Scholar 

  • Hansen J, Kordower J, Fiandaca M, Jiao S, Notter M, Gash D (1988) Adrenal medullary autografts into the basal ganglia of Cebus monkeys: graft viability and fine structure. Exp Neurol 102: 65–75

    Article  PubMed  CAS  Google Scholar 

  • Hemmendinger LM, Garber BB, Hoffman PC, Heller A (1981a) Selective association of embryonic murine mesencephalic dopamine neurons in vitro. Brain Res 222: 417–422

    Article  PubMed  CAS  Google Scholar 

  • Hemmendinger LM, Garber BB, Hoffman PC, Heller A (1981b) Target neuron-specific process formation by embryonic mesencephalic dopamine neurons in vitro. Proc Natl Acad Sci USA 78: 1264–1268

    Article  PubMed  CAS  Google Scholar 

  • Herkenham M, Moon-Edley S, Stuart J (1984) Cell clusters in the nucleus accumbens of the rat, and the mosaic relationship of opiate receptors, acetylcholinesterase and subcortical afferent terminations. Neuroscience 11: 561–593

    Article  PubMed  CAS  Google Scholar 

  • Isacson O, Brundin P, Kelly PAT, Gage FH, Björklund A (1984) Functional neuronal replacement by grafted striatal neurons in the ibotenic acid-lesioned rat striatum. Nature 311: 458–460

    Article  PubMed  CAS  Google Scholar 

  • Isacson O, Brundin P, Gage FH, Björklund A (1985) Neural grafting in a rat model of Huntington’s disease: progressive neurochemical changes after neostriatal ibotenic lesions and striatal tissue grafting. Neuroscience 16: 799–817

    Article  PubMed  CAS  Google Scholar 

  • Iversen SD, Dunnett SB (1990) Functional organization of striatum as studied with neural grafts. Neuropsychologia 28: 601–626

    Article  PubMed  CAS  Google Scholar 

  • Jimenez-Costellanos J, Graybiel AM (1987) Subdivisions of the dopamine-containing A8-A9-A10 complex identified by their differential mesostriatal innervation of striosomes and extrastriosomal matrix. Neuroscience 23: 223–242

    Article  Google Scholar 

  • Johnson D, Nogueira-Araujo G de C (1981) A simple method of reducing the fading of immunofluorescence during microscopy. J Immunol Methods 43: 349–350

    Article  PubMed  CAS  Google Scholar 

  • Kordower JH, Cochran E, Penn RD, Goetz CG (1991) Putative chromaffin cell survival and enhanced host derived-TH-fiber innervation following a functional adrenal medulla autograft for Parkinson’s disease. Ann Neurol 29: 405–412

    Article  PubMed  CAS  Google Scholar 

  • Labandeira-Garcia JL, Wictorin K, Cunningham ET, Björklund A (1991) Development of intrastriatal striatal grafts and their afferents innervation from the host. Neuroscience 42: 4507–426

    Article  Google Scholar 

  • Lin L-FH, Doherty DH, Lile JD, Bektesh S, Collins F (1993) GDNF: a glial cell line-derived neurotrophic factor for midbrain dopaminergic neurons. Science 260: 1130–1132

    PubMed  CAS  Google Scholar 

  • Lindner MD, Winn SR, Baetge EE, Hammang JP, Gentile FT, Doherty E, McDermott PE, Frydel B, Ullman MD, Schallert T, DF E (1995) Implantation of encapsulated cathecholamine and GDNF-producing cells in rats with unilateral dopamine depletions and parkinsonian syndroms. Exp Neurol 132: 62–76

    Article  PubMed  CAS  Google Scholar 

  • Liu F-C, Graybiel AM, Dunnett SB, Baughman RW (1990) Intrastriatal grafts derived from fetal striatal primordia. II. Reconstruction of cholinergic and dopaminergic system. J Comp Neurol 295: 1–14

    Article  PubMed  CAS  Google Scholar 

  • Liu F-C, Dunnett SB, Graybiel AM (1992) Influence of mesostriatal afferents on the development and transmitter regulation of intrastriatal grafts derived from embryonic striatal primordia. J Neurosci 12: 4281–4297

    PubMed  CAS  Google Scholar 

  • Naimi S, Jeny R, Hantraye P, Peschanski M, Riche D (1996) Ontogeny of human striatal DARPP-32 neurons in fetuses and following xenografting to the adult rat brain. Exp Neurol 137: 15–25

    Article  PubMed  CAS  Google Scholar 

  • Niijima K, Araki M, Ogawa M, Nagastu I, Sato F, Kimura H, Yoshida M (1990) Enhanced survival of cultured dopamine neurons by treatment with soluble extracts from chemically deafferented striatum of adult rat brain. Brain Res 528: 151–154

    Article  PubMed  CAS  Google Scholar 

  • Nikkhah G, Odin P, Smits A, Tingström A, Othberg A, Brundin P, Funa K, Lindvall O (1993) Platelet-derived growth factor promotes survival of rat and human mesencephalic dopamine neurons in culture. Exp Brain Res 92: 516–523

    Article  PubMed  CAS  Google Scholar 

  • Olson L, Seiger Å, Fuxe K (1972) Heterogeneity of striatal and limbic dopamine innervation: Highly fluorescent islands in developing and adult rats. Brain Res 44: 283–288

    Article  PubMed  CAS  Google Scholar 

  • Østergaard K, Schou JP, Zimmer J (1990) Rat ventral mesencephalon grown as organotypic slice cultures and co-cultured with striatum, hippocampus, and cerebellum. Exp Brain Res 82: 547–565

    Article  PubMed  Google Scholar 

  • Otto D, Unsicker K (1990) Basic FGF reverses chemical and morphological deficits in the nigrostriatal system of MPTP-treated mice. J Neurosci 10: 1912–1921

    PubMed  CAS  Google Scholar 

  • Pakzaban P, Deacon TW, Burns LH, Isacson O (1993) Increased proportion of acetylcholinesterase-rich zones and improve morphological integration in host striatum of fetal grafts derived from the lateral but not the medial ganglionic eminence. Exp Brain Res 97: 13–22

    Article  PubMed  CAS  Google Scholar 

  • Perlow MJ, Freed WJ, Hoffer BJ, Seiger Å, Olson L, Wyatt RJ (1979) Brain grafts reduce motor abnormalities produced by destruction of nigrostriatal dopamine system. Science 204: 643–647

    PubMed  CAS  Google Scholar 

  • Plunkett RJ, Bankiewicz KS, Cummins AC, Miletich RS, Schwartz JP, Oldfield EH (1990) Long-term evaluation of hemiparkinsonian monkeys after adrenal autografting or cavitation alone. J Neurosurg 73: 918–926

    Article  PubMed  CAS  Google Scholar 

  • Pritzel M, Isacson O, Brundin P, Wiklund L, Björklund A (1986) Afferent and efferent connections of striatal grafts implanted into the ibotenic acid lesioned neostriatum in adult rats. Exp Brain Res 65: 112–126

    Article  PubMed  CAS  Google Scholar 

  • Prochiantz A, U. DP, Dato A, Berger B, Glowinski J (1979) In vitro maturation of mesencephalic dopaminergic neurons from mouse embryos is enhanced in presence of their striatal target cells. Proc Natl Acad Sci USA 76: 5387–5391

    Article  PubMed  CAS  Google Scholar 

  • Sandberg PR, Henault MA, Deckel AW (1986) Effects of multiple striatal transplants in an animal model of Huntington’s disease. Pharmacol Biochem Behav [Suppl] 5: 297–301

    Article  Google Scholar 

  • Sauer H, Rosenblad C, Björklund A (1995) Glial cell line-derived neurotrophic factor but not transforming growth factor β3 prevents delayed degeneration of nigral dopaminergic neurons following striatal 6-hydroxydopamine lesion. Proc Natl Acad Sci USA 92: 8935–8939

    Article  PubMed  CAS  Google Scholar 

  • Schaar DG, Sieber B-A, Dreyfus CF, Black IB (1993) Regional and cell-specific expression of GDNF in rat brain. Exp Neurol 124: 368–371

    Article  PubMed  CAS  Google Scholar 

  • Schmidt RH, Björklund A, Stenevi U (1981) Intracerebral grafting of dissociated CNS tissue suspensions: a new approach for neuronal transplantation to deep brain sites. Brain Res 218: 347–356

    Article  PubMed  CAS  Google Scholar 

  • Seiger Å, Olson L (1973) Late prenatal ontogeny of central monoamine neurons in the rat: fluorescence histochemical observations. Z Anat Entwickl Gesch 140: 281–318

    Article  CAS  Google Scholar 

  • Seroogy KB, Lundgren KH, Lee DC, Guthrie KM, Gall CM (1993) Cellular localization of transforming growth factor-α mRNA in rat forebrain. J Neurochem 60: 1777–1782

    PubMed  CAS  Google Scholar 

  • Sirinathsinghji DJS, Mayer E, Fernandez JM, Dunnett SB (1993) The localization of cholecystokinin mRNA in embryonic striatal tissue grafts: further evidence for the presence of non-striatal cells. Neuroreport 4: 659–662

    PubMed  CAS  Google Scholar 

  • Smits A, Odin P, Duan W-M, Brundin P, Widner H, Heldin C-H, Lindvall O, Funa K (1993) Expression of platelet-derived growth factor in and around intrastriatal embryonic mesencephalic grafts. Cell Transplant 2: 151–162

    PubMed  CAS  Google Scholar 

  • Strömberg I, Bickford (1996) Reduced aging effects of striatal neuronal discharge rate by aged ventral mesencephalic grafts. Neuroreport 7: 693–696

    PubMed  Google Scholar 

  • Strömberg I, Humpel C (1995) Expression of BDNF andtrkB mRNAs in comparison to dopamine D1 and D2 receptor mRNAs and tyrosine hydroxylase-immunoreactivity in nigrostriatal in oculo co-grafts. Brain Res Dev Brain Res 84: 215–224

    Article  PubMed  Google Scholar 

  • Strömberg I, Johansson M (1994) Reinitiated growth from mature ventral mesencephalon: an in oculo transplant study of nigrostriatal co-grafts. Exp Brain Res 101: 73–85

    Article  PubMed  Google Scholar 

  • Strömberg I, Björklung L, Johansson M, Tomac A, Collins F, Olson L, Hoffer B, Humpel C (1993) Glial cell-derived neurotrophic factor (GDNF) is expressed in the developing but not adult striatum and stimulates developing dopamine neurons in vivo. Exp Neurol 124: 401–412

    Article  PubMed  Google Scholar 

  • Takashima H, Walker BR, Cannon-Spoor HE, Freed WJ (1993) Kainic acid lesions increase reafferentation of the striatum by substantia nigra grafts. Brain Res 621: 71–78

    Article  PubMed  CAS  Google Scholar 

  • Tennyson VM, Barrett RE, Cohen G, Cote L, Heikkila R, Mytilineou C (1972) The developing neostriatum of the rabbit: correlation of fluorescence histochemistry, electron microscopy, endogenous dopamine levels, and [3H]dopamine uptake. Brain Res 46: 251–285

    Article  PubMed  CAS  Google Scholar 

  • Tomac A, Lindqvist E, Lin L-F, Ögren SO, Young D, Hoffer BJ, Olson L (1995) Protection and repair of the nigrostriatal dopaminergic system by GDNF in vivo. Nature 373: 335–339

    Article  PubMed  CAS  Google Scholar 

  • Widmer H, Alexi T, Valverde J, Knüsel B, Hefti F (1993) TGFalpha stimulation of phosphatidylinositol hydrolysis in mesencephalic cultures requires neuron-glia interactions. Neuroreport 4: 407–410

    Article  PubMed  CAS  Google Scholar 

  • Wright AK, Arbuthnott GW (1981) The pattern of innervation of the corpus striatum by the substantia nigra. Neuroscience 6: 2063–2067

    Article  PubMed  CAS  Google Scholar 

  • Zhou F, Buchwald N (1989) Connectivities of the striatal grafts in adult rat brain: a rich afference and scant striatonigral efference. Brain Res 504: 15–30

    Article  PubMed  CAS  Google Scholar 

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  1. Department of Neuroscience, Histology, Karolinska Institute, S-17177, Stockholm, Sweden

    L. Björklund & I. Strömberg

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  1. L. Björklund
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  2. I. Strömberg
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Correspondence to L. Björklund.

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Björklund, L., Strömberg, I. Dopaminergic innervation of striatal grafts placed into different sites of normal striatum: differences in the tyrosine hydroxylase immunoreactive growth pattern. Exp Brain Res 113, 13–23 (1997). https://doi.org/10.1007/BF02454138

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