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Re-initiated growth from mature ventral mesencephalon: an in oculo transplant study of nigrostriatal co-grafts

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Abstract

The ability of mature dopaminergic neurons derived from ventral mesencephalon to re-initiate growth after making contact with a non-innervated target was studied using the intra-ocular grafting model. Foetal ventral mesencephalic tissue or brain stem including the locus coeruleus area was grafted to the anterior chamber of the eye. Two weeks, 6 weeks or 1 year after the first implantation, foetal striatal tissue was placed in contact with the nigral graft or grafted alone. The size of the transplants was measured through the cornea. The final size of the striatal grafts was significantly larger when placed alone than when co-grafted with 1-year-old or 6-week-old dopaminergic grafts. Striatum grafted together with 2-week-old nigra was larger than when grafted adjacent to mature substantia nigra, but not significantly so. Nerve fibre outgrowth into the iris from the nigral transplants did not increase after maturation, but the re-innervated area of the host iris progressively increased around the locus coeruleus grafts. Ingrowth of tyrosine hydroxylase (TH) immunoreactive nerve fibres into the striatal grafts was studied 6 weeks after the second implantation. TH immunohistochemistry revealed innervation of the striatal piece in all cases, except for the group where striatum alone was grafted. With the short survival time for cografts of 6 weeks, TH-positive nerve fibres innervated a larger volume, had a patchy appearance and the density was higher in striatum grafted to 2 week-old nigral transplants than that seen in striatal transplants grafted to mature nigral grafts. The patchy pattern of TH-immunoreactive nerve terminals was also seen in striatum co-grafted with 6-week-old or 1-year-old nigral transplants. No difference in striatal innervation volume was detected between those latter two groups. When striatum was implanted adjacent to mature ventral mesencephalon and grown together for 6 months — the longer survival time — the same dense TH-positive innervation as seen in striatum co-grafted with immature nigral tissue at the shorter survival time was found. Additionally, the nigral part of the co-grafts showed increased TH-immunoreactive nerve fibre density. In conclusion, dopaminergic neurites from mature ventral mesencephalic transplants can re-initiate growth if placed in contact with non-innervated striatal tissue. The nigral grafts do not progressively re-innervate the host iris, while locus coeruleus grafts do. The intra-ocular grafting model can be used to study the in vivo effects of trophic factors on mature dopaminergc neurons.

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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  CAS  PubMed  Google Scholar 

  • Allen G, Burns R, Tulipan N, Parker R (1989) Adrenal medullary transplantation to the caudate nucleus in Parkinson's disease. Initial clinical results in 18 patients. Arch Neurol 46:487–491

    Google Scholar 

  • Backlund E-O, Granberg PO, Hamberger B, Knutsson E, Mártensson A, Sedvall G, Seiger Å, Olson L (1985) Transplantation of adrenal medullary tissue to striatum in parkinsonism. First clinical trials. J Neurosurg 62:169–173

    Google Scholar 

  • Beck KD, Knüsel B, Hefti F (1993) The nature of trophic action of brain-derived neurotrophic factor, des(1–3)-insulin-like growth factor-1, and basic fibroblast growth factor on mesencephalic dopaminergic neurons developing in culture. Neuroscience 52:855–866

    Google Scholar 

  • Bernheimer H, Birkmeyer W, Hornykiewicz O, Jellinger K, Seitelberger F (1973) Brain dopamine and the syndromes of Parkinson and Huntington. Clinical, morphological and neurochemical correlations. J Neurol Sci 20:415–455

    Article  CAS  PubMed  Google Scholar 

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

    Google Scholar 

  • Björklund H, Olson L, Seiger Å, Hoffer B (1980) Chronic lead and brain development: intraocular brain grafts as a method to reveal regional and temporal effects in the central nervous system. Environ Res 22:224–236

    Google Scholar 

  • Caroni P, Schwab ME (1988) Two membrane protein fractions from rat central myelin with inhibitory properties for neuron growth and fibroblast spreading. J Cell Biol 16:307–311

    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

    Google Scholar 

  • Clayton GH, Mahalik TJ, Finger TE (1991) Gap-43 and 5B4CAM immunoreactivity during the development of transplanted fetal mesencephalic neurons. Exp Neurol 114:1–10

    Google Scholar 

  • Date I, Notter M, Felten S, Felten D (1990) MPTP-treated young mice but not aging mice show partial recovery of the nigrostriatal dopaminergic system by stereotaxic injection of acidic fibroblast growth factor (aFGF). Brain Res 526:156–160

    Google Scholar 

  • Ebendal T, Olson L, Seiger Å, Hedlund K-O (1980) Nerve growth factors in the rat iris. Nature 286:25–28

    Google Scholar 

  • Ebendal T, Strömberg I, Olson L, Seger Å (1985) Parasympathetic neurotrophic activity in the rat iris: determination after different denervation. Neuroscience 16:181–185

    Google Scholar 

  • Eriksdotter-Nilsson M, Gerhardt G, Seiger Å, Olson L, Hoffer B, Granholm A-C (1988) Age-related alterations in noradrenergic input to the hippocampal formation: structural and functional studies in intraocular transplants. Brain Res 478:269–280

    Google Scholar 

  • Falck B, Hillarp N-Å, Thieme G, Torp A (1962) Fluorescence of catecholamines and related compounds condenced with formaldehyde. J Histochem Cytochem 10:348–354

    CAS  Google Scholar 

  • Faldino G (1924) Sullo sviluppo dei tessuti embrionali omoplastici inestati nella camera anteriore dell'occhio del coniglio. Arc Sci Biol 5:328

    Google Scholar 

  • Ferrarri G, Minozzi M, Toffano G, Leon A, Skaper S (1989) Basic fibroblast growth factor promotes the survival and development of mesencephalic neurons on culture. Dev Biol 133:140–147

    Google Scholar 

  • Freed CR, Breeze RE, Rosenberg NL, Schneck SA, Kriek E, Qi J-X, Lone T, Zhang Y-B, Snyder JA, Wells TH, Olson Ramig L, Thompson L, Maziotta JC, Huang SC, Grafton ST, Brooks D, Sawle G, Schroter G, Ansari AA (1992) Survival of implanted dopamine cells and neurological improvement 12 to 46 months after transplantaion for Parkinson's disease. New Engl J Med 327:1549–1555

    Google Scholar 

  • Friedman WJ, Ibáñez CF, Hallböök F, Persson H, Cain LD, Dreyfus CF, Black IB (1993) Differential actions of neurotrophins in the locus coeruleus and basal forebrain. Exp Neurol 119:72–78

    Google Scholar 

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

    Google Scholar 

  • Giacobini MMJ, Strömberg I, Almström S, Cao Y, Olson L (1993b) Fibroblast growth factors enhance dopamine fibre formation from nigral grafts. Dev Brain Res 75:65–73

    Google Scholar 

  • Goetz CG, Olanow CW, Koller WC, Penn RD, Cahill D, Morantz R, Stebbins G, Tanner CM, Klawans HL, Shannon KM, Comella CL, Witt C, Cox C (1989) Multicenter study of autologous adrenal medullary transplantation to the corpus striatum in patients with advanced Parkinson's disease. New Engl J Med 320:337–341

    Google Scholar 

  • Goetz C, Tanner C, Penn R, Stebbins G3, Gilley D, Shannon K, Klawans H, Comella C, Wilson R, Witt T (1990) Adrenal medullary transplant to the striatum of patients with advanced Parkinson's disease: 1-year motor and psychomotor data. Neurology 40:273–276

    Google Scholar 

  • Hudson J, Bickford P, Johansson M, Hoffer BJ, Strömberg I (1994) Target and neurotransmitter specificity of fetal central nervous system transplants: importance for functional reinnervation. Neuroscience 14:283–290

    Google Scholar 

  • Hyman C, Hofer M, Barde Y-A, Juhasz M, Jancopoulos G, Squinto S, Lindsay R (1991) BNDF is a neurotrophic factor for dopaminergic neurons of the substantia nigra. Nature 350:230–232

    Article  CAS  PubMed  Google Scholar 

  • Hynes M, Berkemeyer L, Poulsen K, Hefti F, Rosenthal A (1993) Neurotrophin-4/5 promotes survival of dopaminergic neurons and is present in embryonic striatum. Soc Neurosci Abstr 19:275.11

    Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  • Knusel B, Michel PP, Schwaber JS, Hefti F (1990) Selective and non-selective stimulation of central cholinergic and dopaminergic development in vitro by nerve growth factor, basic fibroblast growth factor, epidermal growth factor, insulin and the insulin-like growth factors I and II. J Neurosci 10:558–570

    CAS  PubMed  Google Scholar 

  • Knüsel B, Winslow J, Rosenthal A, Burton L, Seid B, Nikolicks K, Hefti F (1991) Promotion of central cholinergic and dopaminergic neuron differentiation by brain-derived neurotrophic factor but not neurotrophin-3. Proc Natl Acad Sci USA 88:961–965

    Google Scholar 

  • Kobayashi RM, Palkovitz M, Kopin IJ, Jacobowitz DM (1977) Biochemical mapping of noradrenergic nerves arising from the rat locus coeruleus. Brain Res 77:269–279

    Google Scholar 

  • Leenders KL, Salmon EP, Tyrrell P, Perani D, Brooks DJ, Sager H, Sager T.J., Sager C.D. Sager M, Frackowiak RSJ (1990) The nigrostriatal dopaminergic system assessed in vivo by positron emission tomography in healthy volonteer subjects and patients with Parkinson's disease. Arch Neurol 47:1290–1298

    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

    CAS  PubMed  Google Scholar 

  • Lindvall O, Björklund A (1974) The organization of the ascending catecholamine neuron systems in the rat brain as revealed by the glyoxylic acid fluorescence method. Acta Physiol Scand [Suppl 412]: 1–48

  • Lindvall O, Backlund E-O, Farde L, Sedvall G, Freedman R, Hoffer B, Nobin A, Seiger Å, Olson L (1987) Transplantation in Parkinson's disease: two cases of adrenal medullary grafts to the putamen. Ann Neurol 22:457–468

    Google Scholar 

  • Lindvall O, Rehncrona S, Gustaavii B, Brundin P, Åstedt B, Widner H, Lindholm T, Björklund A, Leenders K, Rothwell J (1988) Fetal dopamine-rich mesencephalic grafts in Parkinson's disease. Lancet 8626–8627:1483–1484

    Google Scholar 

  • Lindvall O, Brundin P, Widner H, Rehncrona S, Gustavu B, Frackowiak R, Leenders KL, Sawle G, Rothwell JC, Marsden CD (1990) Grafts of fetal dopamine neurons survive and improve motor function in Parkinson's disease. Science 247:575–577

    Google Scholar 

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

    Google Scholar 

  • López-Lozano JJ, Bravo G, Abascal J, Group CPdNT (1991) Grafting of perfused adrenal medullary tissue into the caudate nucleus patients with Parkinson's disease. J Neurosurg 75:234–243

    Google Scholar 

  • Louis J-C, Magal E, Burnham P, Varon S (1993) Cooperative effects of ciliary neurotrophic factor and norepinephrine on tyrosine hydroxylase expression in cultured rat locus coeruleus neurons. Dev Biol 155:1–13

    Google Scholar 

  • Madrazo I, Drucker-Collín R, Díaz V, Martínez-Mata J, Torres C, Becerril JJ (1987) Open microsurgical autograft of adrenal medulla to the right caudate nucleus in two patients with intractable Parkinson's disease. New Engl J Med 316:831–834

    Google Scholar 

  • Magal E, Burnham P, Varon S, Louis J-C (1993) Convergent regulation by ciliary neurotrophic factor and dopamine of tyrosine hydroxylase expression in cultures of rat substantia nigra. Neuroscience 52:867–881

    Google Scholar 

  • Mann DMA, Yates PO (1983) Possible role of neuromelanin in the pathogenesis of Parkinson's disease. Mech Ageing Dev 20:193–203

    Google Scholar 

  • McKeon RJ, Schreiber RC, Rudge JS, Silver J (1991) Reduction of neurite outgrowth in a model of glial scarring following CNS injury is correlated with the expression of inhibitory molecules on reactive astrocytes. J Neurosci 11:3398–3411

    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

    Google Scholar 

  • Nygren L-G, Olson L (1977) A new major projection from locus coeruleus: the main source of noradrenergic nerve terminals in the ventral and dorsal columns of the spinal cord. Brain Res 132:85–93

    Google Scholar 

  • Olanow CW, Koller W, Goetz CG, Stebbins GT, Cahill DW, Gauger LL, Morantz R, Penn RD, Tanner CM, Klawans HL, Shannon KM, Comella CL, Witt T (1990) Autologous transplantation of adrenal medulla in Parkinson's disease. Arch Neurol 47:1286–1289

    Google Scholar 

  • Olson L, Seiger Å, Ålund M (1978) Locus coeruleus fiber growth in oculo induced by trigeminotomy. Med Biol 56:23–27

    Google Scholar 

  • Olson L, Seiger Å, Hoffer B, Taylor D (1979) Isolated catecholamnergic projections from substantia nigra and locus coeruleus to caudate, hippocampus and cerebral cortex formed by intraocular sequential double brain grafts. Exp Brain Res 35:47–67

    Google Scholar 

  • Olson L, Seiger Å, Taylor D, Freedman R, Hoffer B (1980) Conditions for adrenergic hyperinnervation in hippocampus. I. Histochemical evidence from intraocular double grafts. Exp Brain Res 39:277–288

    Google Scholar 

  • Olson L, Seiger Å, Strömberg I (1983) Intraocular transplantation in rodents. A detailed account of the procedure and examples of its use in neurobiology with special reference to brain tissue grafting. In: Federoff S, Hertz L (eds) Advances in cellular neurobiology, vol 4, Academic, New York, pp 407–442

    Google Scholar 

  • Olson L, Backlund E-O, Ebendal T, Freedman R, Hamberger B, Hansson P, Hoffer B, Lindblom U, Meyerson B, Strömberg I, Sydow O, Seiger Å (1991) Intraputaminal infusion of nerve growth factor to support adrenal medullary autografts in Parkinson's disease: one-year follow-up of first clinical trial. Arch Neurol 48:373–381

    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

    Google Scholar 

  • Penn RD, Goetz CG, Tanner CM, Klawans HL, Shannon KM, Comella CL, Witt TR (1988) The adrenal medullary transplant operation for Parkinson's disease: clinical observations in five patients. Neurosurgery 22:999–1004

    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

    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

    Google Scholar 

  • Schultz MW, Chamberlain CG, de Iongh R, McAvoy JW (1993) Acidic and basic FGF in ocular media and lens: implications for lens polarity and growth patterns. Development 118:117–126

    Google Scholar 

  • Schwab ME, Caroni P (1988) Oligodendrocytes and CNS myelin are nonpermissive substrates for neurite growth and fibroblast spreading in vitro. J Neurosci 8:2381–2393

    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

    Google Scholar 

  • Strömberg I, Björklund 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  CAS  PubMed  Google Scholar 

  • Strömberg I, Bygdeman M, Almqvist P (1992) Target-specific outgrowth from human mesencephalic tissue grafted to cortex or ventricle of immunosuppressed rats. J Comp Neurol 315:445–456

    Google Scholar 

  • Wictorin K, Brundin P, Sauer H, Lindvall O, Björklund A (1992) Long distance directed axonal growth from human dopaminergic mesencephalic neuroblasts implanted along the nigrostriatal pathway in 6-hydroxydopamine lesioned adult rats. J Comp Neurol 323:475–494

    Google Scholar 

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

    Google Scholar 

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

    Ingrid Strömberg & Maria Johansson

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  1. Ingrid Strömberg
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  2. Maria Johansson
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Strömberg, I., Johansson, M. Re-initiated growth from mature ventral mesencephalon: an in oculo transplant study of nigrostriatal co-grafts. Exp Brain Res 101, 73–85 (1994). https://doi.org/10.1007/BF00243218

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