Skip to main content

Advertisement

SpringerLink
Log in

Aging of the striatum: mechanisms and interventions

  • Published:
AGE Aims and scope Submit manuscript

Abstract

Motor function declines with increasing adult age. Proper regulation of the balance between dopamine (DA) and acetylcholine (ACh) in the striatum has been shown to be fundamentally important for motor control. Although other factors can also contribute to this age-associated decline, a decrease in the concentration and binding potential of the DA D2 receptor subtype in the striatum, especially in the cholinergic interneurons, are involved in the mechanism. Our studies have shown that gene transfer of the DA D2 receptor subtype with adenoiviral vectors is effective in ameliorating age-associated functional decline of the striatal cholinergic interneurons. These achievements confirm that an age-associated decrease of D2R contributes functional alteration of the interaction of DA and ACh in the striatum and demonstrate that these age-associated changes indeed are modifiable.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7
Fig. 8
Fig. 9

Similar content being viewed by others

References

  • Berg MJ, Ebert B, Willis DK, Host T, Fincham RW, Schottelius DD (1987) Parkinsonism-drug treatment. Part I. Drug Intell Clin Pharm 21:10–21

    PubMed  CAS  Google Scholar 

  • Bolam JP, Bennett BD (1995) Microcircuitry of the neostriatum. In: Ariano MA, Surmeier DJ (eds) Molecular and cellular mechanisms of neostriatal function. Landes, Austin

  • Calabresi P, Centonze D, Gubellini P, Pisani A, Bernardi G (2000) Acetylcholine-mediated modulation of striatal function. Trends Neurosci 23:120–126

    Article  PubMed  CAS  Google Scholar 

  • Carlsson A, Winblad B (1976) Influence of age and time interval between death and autopsy on dopamine and 3-methoxytyramine levels in human basal ganglia. J Neural Transm 38:271–276

    Article  PubMed  CAS  Google Scholar 

  • Carp JS, Anderson RJ (1979) Sensorimotor deficits produced by phenytoin and chlorpromazine in unanesthetized cats. Pharmacol Biochem Behav 10:513–520

    Article  PubMed  CAS  Google Scholar 

  • Chang HT (1988) Dopamine-acetylcholine interaction in the rat striatum: a dual-labeling immunocytochemical study. Brain Res Bull 21:295–230

    Article  PubMed  CAS  Google Scholar 

  • Contant C, Umbriaco D, Garcia S, Watkins KC, Descarries L (1996) Ultrastructural characterization of the acetylcholine innervation in adult rat neostriatum. Neuroscience 71:937–944

    Article  PubMed  CAS  Google Scholar 

  • Das A, Dikshit M, Nath C (2001) Profile of acetylcholinesterase in brain areas of male and female rats of adult and old age. Life Sci 68:1545–1555

    Article  PubMed  CAS  Google Scholar 

  • DeBoer P, Heeringa MJ, Abercrombie ED (1996) Spontaneous release of acetylcholine in striatum is preferentially regulated by inhibitory dopamine D2 receptors. Eur J Pharmacol 317:257–262

    Article  PubMed  CAS  Google Scholar 

  • Delbono O (2003) Neural control of aging skeletal muscle. Aging Cell 2:21–29

    Article  PubMed  CAS  Google Scholar 

  • Della Vedova F, Fumagalli F, Sacchetti G, Racagni G, Brunello N (1992) Age-related variations in relative abundance of alternative spliced D2 receptor mRNAs in brain areas of two rat strains. Brain Res Mol Brain Res 12:357–359

    Article  PubMed  CAS  Google Scholar 

  • Di Chiara G, Morelli M, Consolo S (1994) Modulatory functions of neurotransmitters in the striatum: ACh/dopamine/NMDA interactions. Trends Neurosci 17:228–233

    Article  PubMed  Google Scholar 

  • Dimova R, Vuillet J, Nieoullon A, Kerkerian-Le Goff L (1993) Ultrastructural features of the choline acetyltransferase-containing neurons and relationships with nigral dopaminergic and cortical afferent pathways in the rat striatum. Neuroscience 53:1059–1071

    Article  PubMed  CAS  Google Scholar 

  • Dorfman LJ, Bosley TM (1979) Age-related changes in peripheral and central nerve conduction in man. Neurology 29:38–44

    PubMed  CAS  Google Scholar 

  • Dutta C, Hadley EC, Lexell J (1997) Sarcopenia and physical performance in old age: overview. Muscle Nerve 5:S5–S9

    Article  PubMed  CAS  Google Scholar 

  • Fahn S (2003) Description of Parkinson’s disease as a clinical syndrome. Ann N Y Acad Sci 991:1–14

    PubMed  CAS  Google Scholar 

  • Gage NH, Dunnett SB, Stenevi U, Bjorklund A (1983) Aged rats: recovery of motor impairments by intrastriatal nigral grafts. Science 221:966–969

    Article  PubMed  CAS  Google Scholar 

  • Graybiel AM (1990) Neurotransmitters and neuromodulators in the basal ganglia. Trends Neurosci 13:244–254

    Article  PubMed  CAS  Google Scholar 

  • Han Z, Kuyatt BL, Kochman KA, DeSouza EB, Roth GS (1989) Effect of aging on concentrations of D2-receptor-containing neurons in the rat striatum. Brain Res 498:299–307

    Article  PubMed  CAS  Google Scholar 

  • Henry JM, Roth GS (1984) Effect of aging on recovery of striatal dopamine receptors following N-ethoxycarbonyl-2-ethoxy-1, 2-dihydroquino- line (EEDQ) blockade. Life Sci 35:899–904

    Article  PubMed  CAS  Google Scholar 

  • Henry JM, Joseph JA, Kochman K, Roth GS (1987) Effect of aging on striatal dopamine receptor subtype recovery following N-ethoxycarbonyl -2-ethoxy-1,2-dihydroquinoline blockade and relation to motor function in Wistar rats. Brain Res 418:334–342

    Article  PubMed  CAS  Google Scholar 

  • Herman JP, Lupp A, Abrous N, Le Moal M, Hertting G, Jackisch R (1988) Intrastriatal dopaminergic grafts restore inhibitory control over striatal cholinergic neurons. Exp Brain Res 73:236–248

    Article  PubMed  CAS  Google Scholar 

  • Ikari H, Zhang L, Chernak JM, Mastrangeli A, Kato S, Kuo H, Crystal RG, Ingram DK, Roth GS (1995) Adenovirus-mediated gene transfer of dopamine D2 receptor cDNA into rat striatum. Brain Res Mol Brain Res 34:315–320

    Article  PubMed  CAS  Google Scholar 

  • Ingram DK, Ikari H, Umegaki H, Chernak JM, Roth GS (1998) Application of gene therapy to treat age-related loss of dopamine D2 receptor. Exp Gerontol 33:793–804

    Article  PubMed  CAS  Google Scholar 

  • Jackisch R, Duschek M, Neufang B, Rensing H, Hertting G, Herman JP (1991) Long-term survival of intrastriatal dopaminergic grafts: modulation of acetylcholine release by graft-derived dopamine. J Neurochem 57:267–276

    Article  PubMed  CAS  Google Scholar 

  • Joseph JA, Roth GS (1988a) Upregulation of striatal dopamine receptors and improvement of motor performance in senescence. Ann N Y Acad Sci 515:355–356

    Article  PubMed  CAS  Google Scholar 

  • Joseph JA, Roth GS (1988b) Altered striatal dopaminergic and cholinergic reciprocal inhibitory control and motor behavioral decrements in senescence. Ann N Y Acad Sci 521:110–122

    Article  PubMed  CAS  Google Scholar 

  • Joseph JA, Roth GS, Strong R (1990) The striatum, a microcosm for the examination of age-related alterations in the CNS. Review of biological research in aging. Liss, New York

    Google Scholar 

  • Kaneko S, Hikida T, Watanabe D, Ichinose H, Nagatsu T, Kreitman RJ, Pastan I, Nakanishi S (2000) Synaptic integration mediated by striatal cholinergic interneurons in basal ganglia function. Science 289:633–637

    Article  PubMed  CAS  Google Scholar 

  • Kolb B, Forgie M, Gibb R, Gorny G, Rowntree S (1998) Age, experience and the changing brain. Neurosci Biobehav Rev 22:143–159

    Article  PubMed  CAS  Google Scholar 

  • Kozlowski MR, Marshall JF (1981) Plasticity of neostriatal metabolic activity and behavioral recovery from nigrostriatal injury. Exp Neurol 74:318–323

    Article  PubMed  CAS  Google Scholar 

  • Kubota Y, Inagaki S, Shimada S, Kito S, Eckenstein F, Tohyama M (1987) Neostriatal cholinergic neurons receive direct synaptic inputs from dopaminergic axons. Brain Res 413:179–184

    Article  PubMed  CAS  Google Scholar 

  • Kurotani S, Umegaki H, Ishiwata K, Suzuki Y, Iguchi A (2003) The age-associated changes of dopamine-acetylcholine interaction in the striatum. Exp Gerontol 38:1009–1013

    Article  PubMed  CAS  Google Scholar 

  • Lapper SR, Bolam JP (1992) Input from the frontal cortex and the parafascicular nucleus to cholinergic interneurons in the dorsal striatum of the rat. Neuroscience 51:533–545

    Article  PubMed  CAS  Google Scholar 

  • Lexell J (1997) Evidence for nervous system degeneration with advancing age. J Nutr 127:1011S–1013S

    PubMed  CAS  Google Scholar 

  • Marshall JF, Berrios N (1979) Movement disorders of aged rats: reversal by dopamine receptor stimulation. Science 206:477–479

    Article  PubMed  CAS  Google Scholar 

  • Maurice N, Mercer J, Chan CS, Hernandez-Lopez S, Held J, Tkatch T, Surmeier DJ (2004) D2 dopamine receptor-mediated modulation of voltage-dependent Na+ channels reduces autonomous activity in striatal cholinergic interneurons. J Neurosci 24:10289–10301

    Article  PubMed  CAS  Google Scholar 

  • Mensah PL (1980) Distribution of the largest neuron in mouse caudate-putamen nucleus: its position in large-cell–medium-cell clusters. Exp Brain Res 38:267–271

    Article  PubMed  CAS  Google Scholar 

  • Morgan DG, Finch CE (1988) Dopaminergic changes in the basal ganglia. A generalized phenomenon of aging in mammals. Ann N Y Acad Sci 515:145–160

    Article  PubMed  CAS  Google Scholar 

  • Norman AB, Battaglia G, Creese I (1987) Differential recovery rates of rat D2 dopamine receptors as a function of aging and chronic reserpine treatment following irreversible modification: a key to receptor regulatory mechanisms. J Neurosci 7:1484–1491

    PubMed  CAS  Google Scholar 

  • Ogawa N, Asanuma M, Kondo Y, Nishibayashi S, Mori A (1994) Reduced choline acetyltransferase activity and muscarinic M1 receptor levels in aged Fisher 344 rat brains did not parallel their respective mRNA levels. Brain Res 658:87–92

    Article  PubMed  CAS  Google Scholar 

  • Ogawa O, Umegaki H, Ishiwata K, Asai Y, Ikari H, Oda K, Toyama H, Ingram DK, Roth GS, Iguchi A, Senda M (2000) In vivo imaging of adenovirus-mediated over-expression of dopamine D2 receptors in rat striatum by positron emission tomography. Neuroreport 11:743–748

    Article  PubMed  CAS  Google Scholar 

  • Pickel VM, Chan J (1990) Spiny neurons lacking choline acetyltransferase immunoreactivity are major targets of cholinergic and catecholaminergic terminals in rat striatum. J Neurosci Res 25:263–280

    Article  PubMed  CAS  Google Scholar 

  • Pickel VM, Chan J (1991) Plasmalemmal appositions between cholinergic and non-cholinergic neurons in rat caudate-putamen nuclei. Neuroscience 41:459–472

    Article  PubMed  CAS  Google Scholar 

  • Pisani A, Bonsi P, Centonze D, Calabresi P, Bernardi G (2000) Activation of D2-like dopamine receptors reduces synaptic inputs to striatal cholinergic interneurons. J Neurosci 20:RC69

    PubMed  CAS  Google Scholar 

  • Pisani A, Bonsi P, Picconi B, Tolu M, Giacomini P, Scarnati E (2001) Role of tonically-active neurons in the control of striatal function: cellular mechanisms and behavioral correlates. Prog Neuropsychopharmacol Biol Psychiatry 25:211–213

    Article  PubMed  CAS  Google Scholar 

  • Potvin AR, Syndulko K, Tourtellotte WW, Lemmon JA, Potvin JH (1980) Human neurologic function and the aging process. J Am Geriatr Soc 28:1–9

    PubMed  CAS  Google Scholar 

  • Puschban Z, Scherfler C, Granata R, Laboyrie P, Quinn NP, Jenner P, Poewe W, Wenning GK (2000) Autoradiographic study of striatal dopamine re-uptake sites and dopamine D1 and D2 receptors in a 6-hydroxydopamine and quinolinic acid double-lesion rat model of striatonigral degeneration (multiple system atrophy) and effects of embryonic ventral mesencephalic, striatal or co-grafts. Neuroscience 95:377–388

    Article  PubMed  CAS  Google Scholar 

  • Pycock CJ (1980) Turning behaviour in animals. Neuroscience 5:461–514

    Article  PubMed  CAS  Google Scholar 

  • Rech RH, Borys HK, Moore KE (1966) Alterations in behavior and brain catecholamine levels in rats treated with alpha-methyltyrosine. J Pharmacol Exp Ther 153:412–499

    PubMed  CAS  Google Scholar 

  • Roth GS, Joseph JA (1994) Cellular and molecular mechanisms of impaired dopaminergic function during aging. Ann N Y Acad Sci 719:129–135

    Article  PubMed  CAS  Google Scholar 

  • Sherman KA, Friedman E (1990) Pre- and post-synaptic cholinergic dysfunction in aged rodent brain regions: new findings and an interpretative review. Int J Dev Neurosci 8:689–708

    Article  PubMed  CAS  Google Scholar 

  • Stoof JC, Drukarch B, de Boer P, Westerink BH, Groenewegen HJ (1992) Regulation of the activity of striatal cholinergic neurons by dopamine. Neuroscience 47:755–770

    Article  PubMed  CAS  Google Scholar 

  • Stark AK, Pakkenberg B (2004) Histological changes of the dopaminergic nigrostriatal system in aging. Cell Tissue Res 318:81–92

    Article  Google Scholar 

  • Tepper JM, Bolam JP (2004) Functional diversity and specificity of neostriatal interneurons. Curr Opin Neurobiol 14:685–689

    Article  PubMed  CAS  Google Scholar 

  • Umegaki H, Chernak JM, Ikari H, Roth GS, Ingram DK (1997) Rotational behavior produced by adenovirus-mediated gene transfer of dopamine D2 receptor into rat striatum. Neuroreport 8:3553–3558

    Article  PubMed  CAS  Google Scholar 

  • Umegaki H, Ishiwata K, Ogawa O, Ingram DK, Roth GS, Yoshimura J, Oda K, Matsui-Hirai H, Ikari H, Iguchi A, Senda M (2002) In vivo assessment of adenoviral vector-mediated gene expression of dopamine D(2) receptors in the rat striatum by positron emission tomography. Synapse 43:195–200

    Article  PubMed  CAS  Google Scholar 

  • Umegaki H, Ishiwata K, Ogawa O, Ingram DK, Roth GS, Oda K, Kurotani S, Kawamura K, Wang WF, Ikari H, Senda M, Iguchi A (2003) Longitudinal follow-up study of adenoviral vector-mediated gene transfer of dopamine D2 receptors in the striatum in young, middle-aged, and aged rats: a positron emission tomography study. Neuroscience 121:479–486

    Article  PubMed  CAS  Google Scholar 

  • Umegaki H, Yamaguchi Y, Ishiwata K, Ingram DK, Roth GS, Iguchi A (2006) Functional recovery of the striatal cholinergic system in aged rats by adenoviral vector-mediated gene transfer of dopamine D2 receptor. Mech Ageing Dev 127:813–815

    Article  PubMed  CAS  Google Scholar 

  • Wang L, Albrecht MA, Wurtman RJ (2007) Dietary supplementation with uridine-5′-monophosphate (UMP), a membrane phosphatide precursor, increases acetylcholine level and release in striatum of aged rat. Brain Res 1133:42–48

    Article  PubMed  CAS  Google Scholar 

  • Weiss B, Chen JF, Zhang S, Zhou LW (1992) Developmental and age-related changes in the D2 dopamine receptor mRNA subtypes in rat brain. Neurochem Int 20:49S–58S

    Article  PubMed  CAS  Google Scholar 

  • Wu CF, Bertorelli R, Sacconi M, Pepeu G, Consolo S (1988) Decrease of brain acetylcholine release in aging freely-moving rats detected by microdialysis. Neurobiol Aging 9:357–361

    Article  PubMed  CAS  Google Scholar 

  • Yan Z, Song WJ, Surmeier J (1997) D2 dopamine receptors reduce N-type Ca2+ currents in rat neostriatal cholinergic interneurons through a membrane-delimited, protein-kinase-C-insensitive pathway. J Neurophysiol 77:1003–1015

    PubMed  CAS  Google Scholar 

  • Zambrzycka A, Alberghina M, Strosznajder JB (2002) Effects of aging and amyloid-beta peptides on choline acetyltransferase activity in rat brain. Neurochem Res 27:277–281

    Article  PubMed  CAS  Google Scholar 

  • Zhang L, Ravipati A, Joseph J, Roth GS (1995) Aging-related changes in rat striatal D2 receptor mRNA-containing neurons: a quantitative nonradioactive in situ hybridization study. J Neurosci 15:1735–1740

    PubMed  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Geriatrics, Nagoya University Graduate School of Medicine, 65 Tsuruma-cho, Showa-ku, Nagoya, Aichi, Japan

    Hiroyuki Umegaki

  2. GeroScience, Inc., Pylesville, MD, 21132, USA

    George S. Roth

  3. Nutritional Neuroscience and Aging Laboratory, Pennington Biomedical Research Center, Louisiana State University System, 6400 Perkins Road, Baton Rouge, LA, 70808, USA

    Donald K. Ingram

Authors
  1. Hiroyuki Umegaki
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. George S. Roth
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Donald K. Ingram
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Hiroyuki Umegaki.

About this article

Cite this article

Umegaki, H., Roth, G.S. & Ingram, D.K. Aging of the striatum: mechanisms and interventions. AGE 30, 251–261 (2008). https://doi.org/10.1007/s11357-008-9066-z

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11357-008-9066-z

Keywords

Search

Navigation