Compensation of Lesion-Induced Changes in Cerebral Metabolism and Behaviour by Striatal Neural Implants in a Rat Model of Huntington’s Disease

  • O. Isacson
  • P. Brundin
  • F. H. Gage
  • A. Björklund
Part of the Advances in Behavioral Biology book series (ABBI, volume 28)


There now exists ample evidence that the capacity of the adult CNS for functional recovery after large long-term lesions can be promoted by implants of foetal brain tissue (see, e.g., Björklund and Stenevi, 1979; Björklund et al., 1980; Dunnett et al., 1981a,b, 1982; Perlow et al., 1979; Gash and Sladek, 1979; Freed et al., 1980; Krieger et al., 1980; Gage et al., 1983, 1984; Deckel et al., 1983; Labbe et al., 1983; Isacson et al., 1984; Fine et al., this volume). The use of neural grafting as an experimental technique complements lesion and stimulation experiments in neurobiology. In the assessment of lesion-induced changes in the rat it has been investigated to what extent the grafting of neural tissue to the young lesioned or aged impaired animal can create a sufficient condition for functional recovery (see Björklund et al., 1983; Gage et al., 1983, 1984). Functional recovery after lesion-induced changes has been correlated with histological, neurochemical, physiological and metabolic parameters sometimes giving new insights into the mode of operation of certain neural circuitries or transmitter systems.


Ventral Tegmental Area Globus Pallidus Kainic Acid Ibotenic Acid Glutamic Acid Decarboxylase Activity 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. Aguayo, A.J., Björklund, A., Stenevi, U., and Carlstedt, T., 1984, Fetal mesencephalic neurons survive and extend long axons across PNS grafts inserted into the adult rat striatum. Neurosci. Lett., 45:53.CrossRefGoogle Scholar
  2. Aldinio, C., French, E.D. and Schwarcz, R., 1983, The effects of intra hippocampal ibotenic acid and their blockade by (-)2-amino-7 phospho-nohepatonic acid: morphological and electroencephalographical analysis. Exp. Brain Res., 51:36.CrossRefGoogle Scholar
  3. Bird, E.D., 1980, Chemical pathology of Huntington’s disease, Ann. Rev. Pharmacol. Toxicol., 20:533.CrossRefGoogle Scholar
  4. Björklund, A., Schmidt, R.H., and Stenevi, U., 1980, Functional reinnervation of the neostriatum in the adult rat by use of intraparenchymal grafting of dissociated cell suspensions from the substantia nigra, Cell Tiss. Res., 212:39.CrossRefGoogle Scholar
  5. Björklund, A., and Stenevi, U., 1979, Reconstruction of the nigro striatal dopamine pathways by intracerebral nigral transplants, Brain Res., 177:555.CrossRefGoogle Scholar
  6. Björklund, A., and Stenevi, U., 1981, In vivo evidence for a hippocampal adrenergic neurotrophic factor specifically released on septal deafferentation. Brain Res., 229:403.CrossRefGoogle Scholar
  7. Björklund, A., Stenevi, U., Schmidt, R.H., Dunnett, S.B. and Gage, F.H., 1983, Intracerebral grafting of neuronal cell suspensions. Acta Physiol. Scand., Suppl. 522.Google Scholar
  8. Brundin, P., Isacson, O., and Björklund, A., 1985, Monitoring of cell viability in suspensions of embryonic CNS tissue and its use as a criterion for intracerebral graft survival. Brain Res, (in press).Google Scholar
  9. Bruyn, G.W., 1982, Neurotransmitters in Huntington’s Chorea — a clinician’s view. Prog. Brain Res., 55:445.CrossRefGoogle Scholar
  10. Chase, T.N., 1979, Rational approaches to the pharmacotherapy of chorea, in: “The basal ganglia”, M.D. Yahr, ed., Raven Press, New York.Google Scholar
  11. Coyle, J.T., and Schwarze, R., 1976, Lesions of striatal neurones with kainic acid provides a model for Huntington’s chorea. Nature, 263:244.CrossRefGoogle Scholar
  12. Coyle, J.T., and Schwarze, R., 1983, The use of excitatory amino acids as selective neurotoxins. in: “Handbook of Chemical Neuroanatomy”, Vol. 1, A. Björklund and T. Hökfelt, eds., Elsevier Science Publishers, Amsterdam.Google Scholar
  13. David, S., and Aguayo, A.J., 1981, Axonal elongation into PNS “bridges” after CNS injury in adult rats. Science, 214:931.CrossRefGoogle Scholar
  14. Dawbarn, D., Brundin, P., Isacson, O., Gage, F.H., Emson, P.C., and Björklund, A., 1985, Striatal transplants in ibotenic acid lesioned rats: survival of neurones and development of peptide immunoreactivity (submitted to J. Neurosci.).Google Scholar
  15. Deckel, A.W., Robinson, R.G., Coyle, J.R., and Sanberg, P.R., 1983, Reversal of long-term locomotor abnormalities in the kainic acid model of Huntington’s disease by day 18 fetal striatal implants. Eur. J. Pharm., 93:287.CrossRefGoogle Scholar
  16. Dunnett, S.B., Björklund, A., Stenevi, U., and Iversen, S.D., 1981a, Behavioural recovery following transplantation of substantia nigra in rats subjected to 6–0HDA lesions of the nigrostriatal pathway. I. Unilateral lesions. Brain Res., 215:147.CrossRefGoogle Scholar
  17. Dunnett, S.B., Björklund, A., Stenevi, U., and Iversen, S.D., 1981b, Grafts of embryonic substantia nigra reinnervating the ventrolateral striatum ameliorate sensorimotor impairments and akinesia in rats with 6-OHDA lesions of the nigrostriatal pathway. Brain Res., 229:209.CrossRefGoogle Scholar
  18. Dunnett, S.B., and Iversen, S.D., 1981, Learning impairments following selective kainic acid-induced lesions within the neostriatum of rats. Behav. Brain Res., 2:189.CrossRefGoogle Scholar
  19. Dunnett, S.B., Low, W.C., Iversen, S.D., Stenevi, U., and Björklund, A., 1982, Septal transplants restore maze learning in rats with fornix-fimbria lesions. Brain Res., 251:335.CrossRefGoogle Scholar
  20. Duvoisin, R.C., Chokroverty, S., Lepore, F., and Nicklas, W., 1983, Glutamate dehydrogenase deficiency in patients with olivopontocerebellar atrophy. Neurology, 33:1322.CrossRefGoogle Scholar
  21. Fonnum, F., 1975, A rapid radiochemical method for the determination of choline acetyltransferase. J. Neurochem., 24:407.CrossRefGoogle Scholar
  22. Fonnum, F., Storra-Mathisen, J., and Walberg, F., 1970, Glutamate decarboxylase in inhibitory neurons. A study of the enzyme in Purkinje cell axons and boutons in the cat. Brain Res., 20:259.CrossRefGoogle Scholar
  23. Freed, W.J., Perlow, M.J., Karoum, F., Seiger, A., Olson, L., Hoffer, B.J., and Wyatt, R.J., 1980, Restoration of dopaminergic function by grafting of fetal rat substantia nigra to the caudate nucleus: long-term behavioural, biochemical amd histochemical studies. Ann. Neurol., 8:510.CrossRefGoogle Scholar
  24. Gage, F.H., Björklund, A., and Stenevi, U., 1984, Denervation releases a neuronal survival factor in adult rat hippocampus. Nature, 308:637.CrossRefGoogle Scholar
  25. Gage, F.H., Dunnett, S.B., Björklund, A., and Stenevi, U., 1983, Aged rats: Recovery of motor coordination impairments by intrastriatal nigral grafts. Science, 221:966.CrossRefGoogle Scholar
  26. Gash, D., Sladek, J.R., and Sladek, C.D., 1980, Functional development of grafted vasopressin neurons. Science, 220:1367.CrossRefGoogle Scholar
  27. Glick, S.D., and Cox, R.D., 1978, Nocturnal rotation in normal rats: correlation with an amphetamine-induced rotation and effects of nigrostriatal lesions. Brain Res., 150:149.CrossRefGoogle Scholar
  28. Graybiel, A.M., and Ragsdale, C.W., 1983, Biochemical anatomy of the striatum. in: “Chemical neuroanatomy”, P.C. Emson, ed., Raven Press, New York.Google Scholar
  29. Isacson, O., Brundin, P., Dawbarn, D., Kelly, P.A.T., Gage, F.H., Emson, P.C., and Björklund, A., 1985b, Striatal grafts in the ibotenic acid lesioned striatum, in: “Neural grafting in the mammalian CNS”, A. Björklund and U. Stenevi, eds., Elsevier Biomedical Press, Amsterdam (in press).Google Scholar
  30. Isacson, O., Brundin, P., Kelly, P.A.T., Gage, F.H., and Björklund, A., 1984, Functional neuronal replacement by grafted striatal neurones in the ibotenic acid-lesioned rat striatum. Nature, 311:458.CrossRefGoogle Scholar
  31. Isacson, O., Brundin, P., Gage, F.H., and Björklund, A., 1985, Neural grafting in a rat model of Huntington’s disease: Progressive neurochemical changes after neostriatal ibotenate lesion and striatal tissue grafting (submitted to Neuroscience).Google Scholar
  32. Kelly, P.A.T., Graham, D.I., and McCulloch, J., 1982, Specific alterations in local cerebral glucose utilization following striatal lesions. Brain Res., 233:157.CrossRefGoogle Scholar
  33. Kelly, P.H., 1977, Drug-induced motor behaviour, in: “Handbook of Psycho-pharmacology”, Vol. 8, L.L. Iversen and S.D. Iversen, eds., Plenum Press, N.Y.Google Scholar
  34. Kelly, P.H., Seviour, S.D., and Iversen, S.D., 1975, Amphetamine and apo-morphine responses in the rat following 6–0HDA lesions of the nucleus accumbens septi and corpus striatum. Brain Res., 94:507.CrossRefGoogle Scholar
  35. Kimura, H., McGeer, E.G., and McGeer, P.L., 1981, Metabolic alterations in an animal model of Huntington’s disease using the 14C-deoxyglucose methods. J. Neurol. Transmiss. Suppl., 16:103.Google Scholar
  36. Kitai, S.T., 1981, Electrophysiology of the corpus striatum and brain stem integrating systems. In: “Handbook of Physiology. Nervous System II, Motor Control”, V. Brooks, ed. Williams and Wilkins, Baltimore.Google Scholar
  37. Krammer, E.B., 1980, Anterograde and transsynaptic degeneration ‘en cascade’ in basal ganglia introduced by intrastriatal injection of kainic acid: an animal analogue of Huntington’s disease. Brain Res., 1–96:209.CrossRefGoogle Scholar
  38. Krieger, D.T., Perlow, M.J., Gibson, M.J., Dames, T.F., Zimmerman, E.A., Ferin, M., and Charlton, H.M., 1982, Brain grafts reverse hypogonadism of gonadotropin releasing hormone deficency. Nature, 298:468.CrossRefGoogle Scholar
  39. Kromer, L.F., Björklund, A., and Stenevi, U., 1981, Regeneration of the septohippocampal pathway in adult rats is promoted by utilizing embryonic hippocampal implants as bridges. Brain Res., 210:173.CrossRefGoogle Scholar
  40. Kuhl, D.E., Metter, E.J., Riege, W.H., and Markham, Ch., 1984, Patterns of cerebral glucose utilization in Parkinson’s disease and Huntington’s disease. Ann. Neurol., 15:419.CrossRefGoogle Scholar
  41. Kuhl, D.E., Phelps, M., Markham, C., Winter, J., Metter, J., and Riege, W., 1981, Local cerebral glucose metabolism in Huntington’s disease determined by emission computed tomography of 18F flurorodeoxyglu-cose. Cerebral Blood Flow Metab., 1: Suppl. 1, 459.Google Scholar
  42. Labbe, R., Firl, A., Mufson, E.J., and Stein, D.G., 1983, Fetal brain transplants: reduction of cognitive deficits in rats with frontal cortex lesions. Science, 221:470.CrossRefGoogle Scholar
  43. Martinez, J.L., Petty, C., and Messing R.B., 1982, Regional brain uptake of 2-deoxy-D-glucose following training in a discriminated Y-maze avoidance task. J. Comp. Neurol. Physiol. Psychol. 96:721.CrossRefGoogle Scholar
  44. Mason, S.T., Fibiger, H.C., 1979, Kainic lesions of the striatum in rats mimic the spontaneous motor abnormalities of Huntington’s disease. Neuropharmacol., 18:403.CrossRefGoogle Scholar
  45. Matsunami, K., Kageyama, T., and Kubota, K., 1981, Radioactive 2-deoxy-D-glucose incorporation into the prefrontal and premotor cortex of the monkey performing a forelimb movement. Neurosci. Lett., 26:37.CrossRefGoogle Scholar
  46. Matsunami, K., and Kubota, K., 1983, Radioactive deoxyglucose uptake into the prefrontal cortex during a delayed response task of the monkey. Neurosci. Lett., 36:329.CrossRefGoogle Scholar
  47. McLoon, L.K., McLoon, S.C., and Lund, R.S., 1981, Cultured embryonic retinae transplanted to rat brain: Differentiation and formation of projections to host superior colliculus. Brain Res., 226:15.CrossRefGoogle Scholar
  48. Melamed, E., Hefti, F., and Bird, E.D., 1982, Huntington’s chorea is not associated with hyperactivity of nigrostriatal dopaminergic neurons: studies in post-mortem tissues and in rats with kainic acid lesions. Neurology, 32:640.CrossRefGoogle Scholar
  49. McCulloch, J., 1982, Mapping functional alterations in the CNS with (14C)-deoxyglucose. in: “Handbook of Psychopharmacology”, Vol. 15, L.L. Iversen, S.D. Iversen and S.H. Snyder, eds., Plenum Publishing Corp., New York.Google Scholar
  50. McGeer, E.G., and McGeer, P.L., 1976, Duplication of biochemical changes of Huntington’s chorea by intrastriatal injection of glutamic and kainic acids. Nature, 263:517.CrossRefGoogle Scholar
  51. Mogenson, G.J., and Nielsen, M.A., 1983, Evidence that an accumbens to subpallidal GABA-ergic projection contributes to locomotor activity. Brain Res. Bull., 11:309.CrossRefGoogle Scholar
  52. Olney, J.W., 1979, Excitotoxic amino acids and Huntington’s disease, in: “Advances in Neurology”, Vol. 23, Chase, Wexler, Barbeau, eds., Raven Press, N.Y.Google Scholar
  53. Perlow, M.J., Freed, W.J., Hoffer, B.J., Seiger, A., Olson, L., and Wyatt, R.J., 1979, Brain grafts reduce motor abnormalities produced by destruction of nigrostriatal dopamine system. Science, 204:643.CrossRefGoogle Scholar
  54. Pisa, M., Sanberg, P.R., and Fibiger, H.C., 1981, Striatal injections of kainio acid selectively impair serial memory performance in the rat. Exp. Neurol., 74:633.CrossRefGoogle Scholar
  55. Plaitakis, A., Berl, S., and Yahr, M.D., 1982, Abnormal glutamate metabolism in an adult onset degenerative neurological disorder. Science, 216:193.CrossRefGoogle Scholar
  56. Sanberg, P.R., and Fibiger, H.C., 1979, Body weight, feeding and drinking behaviours in rats with kainic acid-induced lesions of striatal neurons -with a note on body weight symptomatology in Huntington’s disease. Exp. Neurol., 66:444.CrossRefGoogle Scholar
  57. Schwartzman, R.J., Greenberg, J., Revich, M., Klose, K.J., and Alexander, G.M., 1981, Functional metabolic mapping of a conditional motor task in primates utilizing 2-(14C) deoxyglucose. Exp. Neurol., 72:153.CrossRefGoogle Scholar
  58. Sokoloff, L., 1977, Relation between physiological function and energy metabolism in the central nervous system, J. Neurochem., 29:13.CrossRefGoogle Scholar
  59. Swanson, L.W., Mogenson, G.J., Gerfen, C.R., and Robinson, P., 1984, Evidence for a projection from the lateral preoptic area and substantia innorainata to the ‘mesencephalic locomotor region’ in the rat. Brain Res., 295:161.CrossRefGoogle Scholar
  60. Whittier, J.R., and Korenyi, C., 1968, Effect of oral fluphenazine on Huntington’s chorea. Int. J. Neuropsychiatr., 4:1.Google Scholar

Copyright information

© Plenum Press, New York 1985

Authors and Affiliations

  • O. Isacson
    • 1
  • P. Brundin
    • 1
  • F. H. Gage
    • 1
  • A. Björklund
    • 1
  1. 1.Department of HistologyUniversity of LundLundSweeden

Personalised recommendations