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.
Similar content being viewed by others
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
References
Arvidsson A, Collin T, Kirik D, Kokaia Z, Lindvall O (2002) Neuronal replacement from endogenous precursors in the adult brain after stroke. Nat Med 8:963–970
Bédard A, Cossette M, Lévesque M, Parent A (2002a) Proliferating cells can differentiate into neurons in the striatum of normal adult monkey. Neurosci Lett 328:213–216
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 16:1917–1924
Bédard A, Parent A (2004) Evidence of newly generated neurons in the human olfactory bulb. Dev Brain Res 151:159–168
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 21:6718–6731
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 99:11464–11469
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 17:6761–6768
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 56:337–344
Carlén M, Cassidy RM, Brismar H, Smith GA, Enquist LW, Frisén J (2002) Functional integration of adult-born neurons. Curr Biol 12:606–608
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 24:2133–2142
Coggeshall RE (1992) A consideration of neural counting methods. Trends Neurosci 15:9–13
Cossette M, Lévesque M, Parent A (1999) Extrastriatal dopaminergic innervation of the human basal ganglia. Neurosci Res 34:51–54
Cossette M, Bédard A, Parent A (2003) Dopaminergic neurons in human striatum and neurogenesis in adult monkey striatum. Ann NY Acad Sci 991:346–349
Cossette M, Lecomte F, Parent A (2005) Morphology and distribution of dopaminergic neurons intrinsic to the human striatum. J Chem Neuroanat 29:1–11
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 16:2649–2658
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 168:415–427
Emmers R, Akert K (1963) A stereotaxic atlas of the brain of the squirrel monkey (Saimiri sciureus). The University of Wisconsin Press, Madison
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 97:14686–14691
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 118:127–138
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 82:8780–8784
Gleeson JG, Lin PT, Flanagan LA, Walsh CA (1999) Doublecortin is a microtubule-associated protein and is widely expressed by migrating neurons. Neuron 23:257–271
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 96:5263–5267
Gould E, Reeves AJ, Graziano MS, Gross CG (1999b) Neurogenesis in the neocortex of adult primates. Science 286:548–552
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 98:10910–10917
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 3:765–770
Greengard P, Allen PB, Nairn AC (1999) Beyond the dopamine receptor: the DARPP-32/protein phosphatase-1 cascade. Neuron 23:435–447
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 92:210–214
Kornack DR, Rakic P (2001) The generation, migration, and differentiation of olfactory neurons in the adult primate brain. Proc Natl Acad Sci USA 98:4752–4757
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 19:3245–3254
Lois C, Alvarez-Buylla A (1994) Long-distance neuronal migration in the adult mammalian brain. Science 264:1145–1148
Luskin MB (1993) Restricted proliferation and migration of postnatally generated neurons derived from the forebrain subventricular zone. Neuron 11:173–189
Mitchell IJ, Cooper AJ, Griffiths MR (1999) The selective vulnerability of striatopallidal neurons. Prog Neurobiol 59:691–719
Mizuno K, Carnahan J, Nawa H (1994) Brain-Derived neurotrophic factor promotes differentiation of striatal GABAergic neurons. Dev Biol 165:243–256
Ouimet CC, Langley-Gullion KC, Greengard P (1998) Quantitative immunocytochemistry of DARPP-32-expressing neurons in the rat caudatoputamen. Brain Res 808:8–12
Parent A (1996) Carpenter’s human neuroanatomy, 9th edn. Williams & Wilkins, Baltimore
Parent A, Fortin M, Côté PY, Cicchetti F (1996) Calcium-binding proteins in primate basal ganglia. Neurosci Res 25:309–334
Parent JM, Vexler ZS, Gong C, Derugin N, Ferriero DM (2002) Rat forebrain neurogenesis and striatal neuron replacement after focal stroke. Ann Neurol 52:802–813
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 21:6706–6717
Porritt MJ, Batchelor PE, Hughes AJ, Kalnins R, Donnan GA, Howells DW (2000) New dopaminergic neurons in Parkinson’s disease striatum. Lancet 356:44–45
Reynolds BA, Tetzlaff W, Weiss S (1992) A multipotent EGF-responsive striatal embryonic progenitor cell produces neurons and astrocytes. J Neurosci 12:4565–4574
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 35:395–425
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 23:292–301
van Praag H, Schinder AF, Christie BR, Toni N, Palmer TD, Gage FH (2002) Functional neurogenesis in the adult hippocampus. Nature 415:1030–1034
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 7:213–222
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 6:1391–1401
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 11:234–245
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 293:493–498
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.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Bédard, A., Gravel, C. & Parent, A. Chemical characterization of newly generated neurons in the striatum of adult primates. Exp Brain Res 170, 501–512 (2006). https://doi.org/10.1007/s00221-005-0233-5
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00221-005-0233-5