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Experimental Brain Research

, Volume 170, Issue 4, pp 501–512 | Cite as

Chemical characterization of newly generated neurons in the striatum of adult primates

  • Andréanne Bédard
  • Claude Gravel
  • André ParentEmail author
Research Article

Abstract

We recently demonstrated the existence of neurogenesis in the striatum of adult monkeys, but the number of striatal neurons generated under normal conditions was too small to establish their chemical phenotype. We therefore used brain-derived neurotrophic factor (BDNF), which promotes neuronal differentiation and survival and induces striatal neurogenesis in rodents, in an attempt to increase the number of newborn neurons in monkey striatum and facilitate their chemical characterization. An adenoviral vector (AdBDNF), encoding the human BDNF cDNA under the control of a strong promoter, was injected into the lateral ventricles (LVs) of adult squirrel monkeys, which were then treated with bromodeoxyuridine (BrdU). Two weeks after viral injection, numerous BrdU-positive cells were found within the striatum and many expressed microtubule-associated protein 2 (MAP-2) and neuronal nuclear protein (NeuN), two markers of mature neurons. Newborn neurons also expressed glutamic acid decarboxylase (GAD65/67), calbindin (CB) and dopamine- and cAMP-regulated phosphoprotein of 32 kDa (DARPP-32), three markers of striatal projection neurons. We found no BrdU-positive neurons displaying the phenotype of striatal interneurons. Numerous BrdU-positive cells located near the subventricular zone (SVZ) coexpressed the migrating neuroblast markers polysialylated neural cell adhesion (PSA-NCAM) and doublecortin (DCX), suggesting that precursor cells could migrate from LVs to striatal parenchyma and develop a neuronal phenotype once they reach the striatum. However, many pairs of BrdU-positive nuclei were observed in the striatal parenchyma, suggesting that newborn neurons could also arise from resident progenitor cells. The present study demonstrates that a single injection of AdBDNF increases the number of newborn neurons into adult primate striatum and that newborn striatal neurons exhibit the chemical phenotype of medium-spiny projection neurons, which are specifically targeted in Huntington’s disease.

Keywords

Brain development Adult neurogenesis Stem cells Basal ganglia Huntington’s disease Neurodegenerative diseases 

Abbreviations

Ad

Adenoviral vector

BDNF

Brain-derived neurotrophic factor

BrdU

Bromodeoxyuridine

CB

Calbindin

ChAT

Choline acetyltransferase

CR

Calretinin

CMV

Cytomegalovirus

CSF

Cerebrospinal fluid

DARPP-32

Dopamine- and cAMP-regulated phosphoprotein of 32 kDa

DCX

Doublecortin

GAD

Glutamic acid decarboxylase

GFAP

Glial fibrillary acidic protein

LV

Lateral ventricle

MAP-2

Microtubule-associated protein 2

MPTP

1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine

NeuN

Neuronal nuclear protein

OB

Olfactory bulb

RMS

Rostral migratory stream

PV

Parvalbumin

PSA-NCAM

Polysialylated neural cell adhesion

SS

Somatostatin

SVZ

Subventricular zone

TH

Tyrosine hydroxylase

TuJ1

β-Tubulin class III

Notes

Acknowledgements

The authors express their gratitude to Dr. Robert Benoit, Montreal General Hospital, for having provided the SS antibody. We also thank M. Lévesque, J.C. Lévesque, A. Lorrain., M. Massouh and C. Paquet for their precious technical help. This research was supported by grant MOP-5781 of the Canadian Institutes for Health Research (CIHR). A. Bédard was the recipient of a CIHR Studentship.

References

  1. Arvidsson A, Collin T, Kirik D, Kokaia Z, Lindvall O (2002) Neuronal replacement from endogenous precursors in the adult brain after stroke. Nat Med 8:963–970CrossRefPubMedGoogle Scholar
  2. Bédard A, Cossette M, Lévesque M, Parent A (2002a) Proliferating cells can differentiate into neurons in the striatum of normal adult monkey. Neurosci Lett 328:213–216CrossRefPubMedGoogle Scholar
  3. Bédard A, Lévesque M, Bernier PJ, Parent A (2002b) The rostral migratory stream in adult squirrel monkeys: contribution of new neurons to the olfactory tubercle and involvement of the antiapoptotic protein Bcl-2. Eur J Neurosci 16:1917–1924CrossRefPubMedGoogle Scholar
  4. Bédard A, Parent A (2004) Evidence of newly generated neurons in the human olfactory bulb. Dev Brain Res 151:159–168CrossRefGoogle Scholar
  5. Benraiss A, Chmielnicki E, Lerner K, Roh D, Goldman SA (2001) Adenoviral brain-derived neurotrophic factor induces both neostriatal and olfactory neuronal recruitment from endogenous progenitor cells in the adult forebrain. J Neurosci 21:6718–6731PubMedGoogle Scholar
  6. Bernier PJ, Bédard A, Vinet J, Lévesque M, Parent A (2002) Newly generated neurons in the amygdala and adjoining cortex of adult primates. Proc Natl Acad Sci USA 99:11464–11469CrossRefPubMedGoogle Scholar
  7. Betarbet R, Turner R, Chockan V, DeLong MR, Allers KA, Walters J, Levey AI, Greenamyre JT (1997) Dopaminergic neuronsintrinsic to the primate striatum. J Neurosci 17:6761–6768PubMedGoogle Scholar
  8. Cameron HA, Woolley CS, McEwen BS, Gould E (1993) Differentiation of newly born neurons and glia in the dentate gyrus of the adult rat. Neuroscience 56:337–344PubMedCrossRefGoogle Scholar
  9. Carlén M, Cassidy RM, Brismar H, Smith GA, Enquist LW, Frisén J (2002) Functional integration of adult-born neurons. Curr Biol 12:606–608CrossRefPubMedGoogle Scholar
  10. Chmielnicki E, Benraiss A, Economides AN, Goldman SA (2004) Adenovirally expressed noggin and brain-derived neurotrophic factor cooperate to induce new medium spiny neurons from resident progenitor cells in the adult striatal ventricular zone. J Neurosci 24:2133–2142CrossRefPubMedGoogle Scholar
  11. Coggeshall RE (1992) A consideration of neural counting methods. Trends Neurosci 15:9–13CrossRefPubMedGoogle Scholar
  12. Cossette M, Lévesque M, Parent A (1999) Extrastriatal dopaminergic innervation of the human basal ganglia. Neurosci Res 34:51–54CrossRefPubMedGoogle Scholar
  13. Cossette M, Bédard A, Parent A (2003) Dopaminergic neurons in human striatum and neurogenesis in adult monkey striatum. Ann NY Acad Sci 991:346–349CrossRefGoogle Scholar
  14. Cossette M, Lecomte F, Parent A (2005) Morphology and distribution of dopaminergic neurons intrinsic to the human striatum. J Chem Neuroanat 29:1–11CrossRefPubMedGoogle Scholar
  15. Craig CG, Tropepe V, Morshead CM, Reynolds BA, Weiss S, van der Kooy D (1996) In vivo growth factor expansion of endogenous subependymal neural precursor cell populations in the adult mouse brain. J Neurosci 16:2649–2658PubMedGoogle Scholar
  16. Dayer AG, Cleaver KM, Abouantoun T, Cameron HA (2005) New GABAergic interneurons in the adult neocortex and striatum are generated from different precursors. J Cell Biol 168:415–427CrossRefPubMedGoogle Scholar
  17. Emmers R, Akert K (1963) A stereotaxic atlas of the brain of the squirrel monkey (Saimiri sciureus). The University of Wisconsin Press, MadisonGoogle Scholar
  18. Fallon J, Reid S, Kinyamu R, Opole I, Opole R, Baratta J, Korc M, Endo TL, Duong A, Nguyen G, Karkehabadhi M, Twardzik D, Patel S, Loughlin S (2000) In vivo induction of massive proliferation, directed migration, and differentiation of neural cells in the adult mammalian brain. Proc Natl Acad Sci USA 97:14686–14691CrossRefPubMedGoogle Scholar
  19. Gauthier LR, Charrin BC, Borrell-Pages M, Dompierre JP, Rangone H, Cordelieres FP, De Mey J, MacDonald ME, Lessmann V, Humbert S, Saudou F (2004) Huntingtin controls neurotrophic support and survival of neurons by enhancing BDNF vesicular transport along microtubules. Cell 118:127–138CrossRefPubMedGoogle Scholar
  20. Gerfen CR, Baimbridge KG, Miller JJ (1985) The neostriatal mosaic: compartmental distribution of calcium-binding protein and parvalbumin in the basal ganglia of the rat and monkey. Proc Natl Acad Sci USA 82:8780–8784PubMedCrossRefGoogle Scholar
  21. Gleeson JG, Lin PT, Flanagan LA, Walsh CA (1999) Doublecortin is a microtubule-associated protein and is widely expressed by migrating neurons. Neuron 23:257–271CrossRefPubMedGoogle Scholar
  22. Gould E, Reeves AJ, Fallah M, Tanapat P, Gross CG, Fuchs E (1999a) Hippocampal neurogenesis in adult Old World primates. Proc Natl Acad Sci USA 96:5263–5267CrossRefPubMedGoogle Scholar
  23. Gould E, Reeves AJ, Graziano MS, Gross CG (1999b) Neurogenesis in the neocortex of adult primates. Science 286:548–552CrossRefPubMedGoogle Scholar
  24. Gould E, Vail N, Wagers M, Gross CG (2001) Adult-generated hippocampal and neocortical neurons in macaques have a transient existence. Proc Natl Acad Sci USA 98:10910–10917CrossRefPubMedGoogle Scholar
  25. Gravel C, Gotz R, Lorrain A, Sendtner M (1997) Adenoviral gene transfer of ciliary neurotrophic factor and brain-derived neurotrophic factor leads to long-term survival of axotomized motor neurons. Nat Med 3:765–770CrossRefPubMedGoogle Scholar
  26. Greengard P, Allen PB, Nairn AC (1999) Beyond the dopamine receptor: the DARPP-32/protein phosphatase-1 cascade. Neuron 23:435–447CrossRefPubMedGoogle Scholar
  27. Kirschenbaum B, Goldman SA (1995) Brain-derived neurotrophic factor promotes the survival of neurons arising from the adult rat forebrain subependymal zone. Proc Natl Acad Sci USA 92:210–214PubMedCrossRefGoogle Scholar
  28. Kornack DR, Rakic P (2001) The generation, migration, and differentiation of olfactory neurons in the adult primate brain. Proc Natl Acad Sci USA 98:4752–4757CrossRefPubMedGoogle Scholar
  29. Lähteinen S, Pitkänen A, Knuutila J, Törönen P, Castrén E (2004) Brain-derived neurotrophic factor signaling modifies hippocampal gene expression during epileptogenesis in transgenic mice. Eur J Neurosci 19:3245–3254CrossRefPubMedGoogle Scholar
  30. Lois C, Alvarez-Buylla A (1994) Long-distance neuronal migration in the adult mammalian brain. Science 264:1145–1148PubMedCrossRefGoogle Scholar
  31. Luskin MB (1993) Restricted proliferation and migration of postnatally generated neurons derived from the forebrain subventricular zone. Neuron 11:173–189CrossRefPubMedGoogle Scholar
  32. Mitchell IJ, Cooper AJ, Griffiths MR (1999) The selective vulnerability of striatopallidal neurons. Prog Neurobiol 59:691–719CrossRefPubMedGoogle Scholar
  33. Mizuno K, Carnahan J, Nawa H (1994) Brain-Derived neurotrophic factor promotes differentiation of striatal GABAergic neurons. Dev Biol 165:243–256CrossRefPubMedGoogle Scholar
  34. Ouimet CC, Langley-Gullion KC, Greengard P (1998) Quantitative immunocytochemistry of DARPP-32-expressing neurons in the rat caudatoputamen. Brain Res 808:8–12CrossRefPubMedGoogle Scholar
  35. Parent A (1996) Carpenter’s human neuroanatomy, 9th edn. Williams & Wilkins, BaltimoreGoogle Scholar
  36. Parent A, Fortin M, Côté PY, Cicchetti F (1996) Calcium-binding proteins in primate basal ganglia. Neurosci Res 25:309–334CrossRefPubMedGoogle Scholar
  37. Parent JM, Vexler ZS, Gong C, Derugin N, Ferriero DM (2002) Rat forebrain neurogenesis and striatal neuron replacement after focal stroke. Ann Neurol 52:802–813CrossRefPubMedGoogle Scholar
  38. Pencea V, Bingaman KD, Wiegand SJ, Luskin MB (2001) Infusion of brain-derived neurotrophic factor into lateral ventricle of the adult rat leads to new neurons in the parenchyma of the striatum, septum, thalamus and hypothalamus. J Neurosci 21:6706–6717PubMedGoogle Scholar
  39. Porritt MJ, Batchelor PE, Hughes AJ, Kalnins R, Donnan GA, Howells DW (2000) New dopaminergic neurons in Parkinson’s disease striatum. Lancet 356:44–45CrossRefPubMedGoogle Scholar
  40. Reynolds BA, Tetzlaff W, Weiss S (1992) A multipotent EGF-responsive striatal embryonic progenitor cell produces neurons and astrocytes. J Neurosci 12:4565–4574PubMedGoogle Scholar
  41. Shetty AK, Turner DA (1998) In vitro survival and differentiation of neurons derived from epidermal growth factor-responsive postnatal hippocampal stem cells: inducing effects of brain-derived neurotrophic factor. J Neurobiol 35:395–425CrossRefPubMedGoogle Scholar
  42. Tonchev AB, Yamashima T, Zhao L, Okano HJ, Okano H (2003) Proliferation of neural and neuronal progenitors after global brain ischemia in young adult macaque monkeys. Mol Cell Neurosci 23:292–301CrossRefPubMedGoogle Scholar
  43. van Praag H, Schinder AF, Christie BR, Toni N, Palmer TD, Gage FH (2002) Functional neurogenesis in the adult hippocampus. Nature 415:1030–1034PubMedCrossRefGoogle Scholar
  44. Ventimiglia R, Mather PE, Jones BE, Lindsay RM (1995) The neurotrophins BDNF, NT-3 and NT-4/5 promote survival and morphological and biochemical differentiation of striatal neurons in vitro. Eur J Neurosci 7:213–222PubMedCrossRefGoogle Scholar
  45. Vilquin JT, Guérette B, Kinoshita I, Roy B, Goulet M, Gravel C, Roy R, Tremblay JP (1995) FK506 immunosuppression to control the immune reactions triggered by first-generation adenovirus-mediated gene transfer. Hum Gene Ther 6:1391–1401PubMedCrossRefGoogle Scholar
  46. Zigova T, Pencea V, Wiegand SJ, Luskin MB (1998) Intraventricular administration of BDNF increases the number of newly generated neurons in the adult olfactory bulb. Mol Cell Neurosci 11:234–245CrossRefPubMedGoogle Scholar
  47. Zuccato C, Ciammola A, Rigamonti D, Leavitt BR, Goffredo D, Conti L, MacDonald ME, Friedlander RM, Silani V, Hayden MR, Timmusk T, Sipione S, Cattaneo E (2001) Loss of huntingtin-mediated BDNF gene transcription in Huntington’s disease. Science 293:493–498CrossRefPubMedGoogle Scholar

Copyright information

© Springer-Verlag 2005

Authors and Affiliations

  • Andréanne Bédard
    • 1
  • Claude Gravel
    • 1
  • André Parent
    • 1
    Email author
  1. 1.Centre de recherche Université Laval Robert-Giffard 2601BeauportCanada

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