Imaging of Dopaminergic Neurons and the Implications for Parkinson’s Disease

  • Wakoto Matsuda


The Systems Biology of Parkinson’s disease (PD) will be underpinned by new measurement techniques. This is particularly true of the pathology of PD, where recent developments in brain imaging have offered new insights into the morphology of dopaminergic (DA) neurons that have profound implications for the special vulnerability and role of this class of neurons. In this chapter, we describe these new morphological measurement techniques and how they contribute to our understanding of PD.

We begin with an overview of the conventional understanding of the morphology of DA neurons, as seen from a historical perspective. We then describe novel imaging techniques that reveal important new structural information concerning DA neurons. In particular, we outline some new methods for labeling DA neurons, together with the technical aspects of labeling and measuring axonal structure.

Detail morphological images of DA neurons derived from this new approach are used to elucidate the role of DA neurons in PD. First, we point out how the new images reveal how DA neurons have a massive axonal arborization in the striatum. This arborization is on a scale not previously known, and of a form that implies both a particular vulnerability and a redundancy in DA neurons. Second, we describe how the imaging results indicate that DA neurons innervate both the striosome and the matrix compartments of the striatum. This dual innervation has implications for reinforcement learning in the basal ganglia and for how normal behavior is driven and how it may be disrupted by Levodopa PD therapies.

The chapter concludes with a summary of how these results contribute to our understanding of PD and how it forms a part of the Systems Biology of PD.


Substantia Nigra Ventral Tegmental Area Infected Neuron Axon Fiber Axonal Arborization 
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.


Competing Interest Statements

The authors declare that they have no competing financial interests.

Acknowledgments This study was supported by Grants-in-Aid for Scientific Research 22500307, 22500308, 22592041, and General Insurance Association of Japan, ZENKYOREN, Mitsui Sumitomo Insurance Welfare Foundation, and Shiga Prefecture Rehabilitation Centre.


  1. 1.
    Alexander GE, Crutcher MD et al (1990) Basal ganglia-thalamocortical circuits: parallel substrates for motor, oculomotor, “prefrontal” and “limbic” functions. Prog Brain Res 85:119–146PubMedCrossRefGoogle Scholar
  2. 2.
    Anden NE, Hfuxe K et al (1966) A quantitative study on the nigro-neostriatal dopamine neuron system in the rat. Acta Physiol Scand 67(3):306–312PubMedCrossRefGoogle Scholar
  3. 3.
    Bjorklund A, Dunnett SB (2007) Dopamine neuron systems in the brain: an update. Trends Neurosci 30(5):194–202PubMedCrossRefGoogle Scholar
  4. 4.
    Blanchet PJ, Calon F et al (1995) Continuous administration decreases and pulsatile administration increases behavioral sensitivity to a novel dopamine D2 agonist (U-91356A) in MPTP-exposed monkeys. J Pharmacol Exp Ther 272(2):854–859PubMedGoogle Scholar
  5. 5.
    Bowen WD, Gentleman S et al (1981) Interconverting mu and delta forms of the opiate receptor in rat striatal patches. Proc Natl Acad Sci U S A 78(8):4818–4822PubMedCrossRefGoogle Scholar
  6. 6.
    Braak H, Ghebremedhin E et al (2004) Stages in the development of Parkinson’s disease-related pathology. Cell Tissue Res 318(1):121–134PubMedCrossRefGoogle Scholar
  7. 7.
    Calabresi P, Centonze D et al (2000) Synaptic transmission in the striatum: from plasticity to neurodegeneration. Prog Neurobiol 61(3):231–265PubMedCrossRefGoogle Scholar
  8. 8.
    Calabresi P, Picconi B et al (2007) Dopamine-mediated regulation of corticostriatal synaptic plasticity. Trends Neurosci 30(5):211–219PubMedCrossRefGoogle Scholar
  9. 9.
    Dahlstroem A, Fuxe K (1964) Evidence for the existence of monoamine-containing neurons in the central nervous system: I. Demonstration of monoamines in the cell bodies of brain stem neurons. Acta Physiol Scand Suppl 232(suppl):231–255Google Scholar
  10. 10.
    Dickson DW (2007) Neuropathology. In: Rajesh Pahwa KEL (ed) Handbook of Parkinson’s disease. Informa Healthcare, New York, pp 195–207Google Scholar
  11. 11.
    Donoghue JP, Herkenham M (1986) Neostriatal projections from individual cortical fields conform to histochemically distinct striatal compartments in the rat. Brain Res 365(2):397–403PubMedCrossRefGoogle Scholar
  12. 12.
    Doya K (2000) Complementary roles of basal ganglia and cerebellum in learning and motor control. Curr Opin Neurobiol 10(6):732–739PubMedCrossRefGoogle Scholar
  13. 13.
    Furuta T, Tomioka R et al (2001) In vivo transduction of central neurons using recombinant Sindbis virus: Golgi-like labelling of dendrites and axons with membrane-targeted fluorescent proteins. J Histochem Cytochem 49(12):1497–1508PubMedCrossRefGoogle Scholar
  14. 14.
    Gauthier J, Parent M et al (1999) The axonal arborization of single nigrostriatal neurons in rats. Brain Res 834(1–2):228–232PubMedCrossRefGoogle Scholar
  15. 15.
    Gauthier-Campbell C, Bredt DS et al (2004) Regulation of dendritic branching and filopodia formation in hippocampal neurons by specific acylated protein motifs. Mol Biol Cell 15(5):2205–2217PubMedCrossRefGoogle Scholar
  16. 16.
    Gerfen CR (1984) The neostriatal mosaic: compartmentalization of corticostriatal input and striatonigral output systems. Nature 311(5985):461–464PubMedCrossRefGoogle Scholar
  17. 17.
    Gerfen CR (1985) The neostriatal mosaic: I. Compartmental organization of projections from the striatum to the substantia nigra in the rat. J Comp Neurol 236(4):454–476PubMedCrossRefGoogle Scholar
  18. 18.
    Gerfen CR (1989) The neostriatal mosaic: striatal patch-matrix organization is related to cortical lamination. Science 246(4928):385–388PubMedCrossRefGoogle Scholar
  19. 19.
    Gerfen CR, Baimbridge KG et al (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 U S A 82(24):8780–8784PubMedCrossRefGoogle Scholar
  20. 20.
    Gerfen CR, Baimbridge KG et al (1987) The neostriatal mosaic: III. Biochemical and developmental dissociation of patch-matrix mesostriatal systems. J Neurosci 7(12):3935–3944PubMedGoogle Scholar
  21. 21.
    Gerfen CR, Herkenham M et al (1987) The neostriatal mosaic: II. Patch- and matrix-directed mesostriatal dopaminergic and non-dopaminergic systems. J Neurosci 7(12):3915–3934PubMedGoogle Scholar
  22. 22.
    Goodwin GC, Graebe SF, Salgado ME (2001) Control system design. Prentice Hall, Englewood Cliffs, 908 pGoogle Scholar
  23. 23.
    Graybiel AM, Ragsdale CW Jr (1978) Histochemically distinct compartments in the striatum of human, monkeys, and cat demonstrated by acetylthiocholinesterase staining. Proc Natl Acad Sci U S A 75(11):5723–5726PubMedCrossRefGoogle Scholar
  24. 24.
    Halliday GM, Tork I (1986) Comparative anatomy of the ventromedial mesencephalic tegmentum in the rat, cat, monkey and human. J Comp Neurol 252(4):423–445PubMedCrossRefGoogle Scholar
  25. 25.
    Herkenham M, Pert CB (1981) Mosaic distribution of opiate receptors, parafascicular projections and acetylcholinesterase in rat striatum. Nature 291(5814):415–418PubMedCrossRefGoogle Scholar
  26. 26.
    Hirsch E, Graybiel AM et al (1988) Melanized dopaminergic neurons are differentially susceptible to degeneration in Parkinson’s disease. Nature 334(6180):345–348PubMedCrossRefGoogle Scholar
  27. 27.
    Ito T, Hioki H et al (2007) Gamma-aminobutyric acid-containing sympathetic preganglionic neurons in rat thoracic spinal cord send their axons to the superior cervical ganglion. J Comp Neurol 502(1):113–125PubMedCrossRefGoogle Scholar
  28. 28.
    Izenwasser S, French D (2002) Tolerance and sensitization to the locomotor-activating effects of cocaine are mediated via independent mechanisms. Pharmacol Biochem Behav 73(4):877–882PubMedCrossRefGoogle Scholar
  29. 29.
    Jellinger KA (2004) Parkinsonism and persistent vegetative state after head injury. J Neurol Neurosurg Psychiatry 75(7):1082; author reply 1082–1083Google Scholar
  30. 30.
    Jimenez-Castellanos J, Graybiel AM (1987) Subdivisions of the dopamine-containing A8-A9-A10 complex identified by their differential mesostriatal innervation of striosomes and extrastriosomal matrix. Neuroscience 23(1):223–242PubMedCrossRefGoogle Scholar
  31. 31.
    Joel D, Weiner I (2000) The connections of the dopaminergic system with the striatum in rats and primates: an analysis with respect to the functional and compartmental organization of the striatum. Neuroscience 96(3):451–474PubMedCrossRefGoogle Scholar
  32. 32.
    Kaneko T, Minami M et al (1995) Immunocytochemical localization of mu-opioid receptor in the rat caudate-putamen. Neurosci Lett 184(3):149–152PubMedCrossRefGoogle Scholar
  33. 33.
    Langer LF, Graybiel AM (1989) Distinct nigrostriatal projection systems innervate striosomes and matrix in the primate striatum. Brain Res 498(2):344–350PubMedCrossRefGoogle Scholar
  34. 34.
    Matsuda W (2008) Axonal arborization of mesocorticolimbic (A10) dopaminergic pathway: a single-cell study. The 31st annual meeting of the Japan neuroscience society, ElsevierGoogle Scholar
  35. 35.
    Matsuda W, Furuta T et al (2009) Single nigrostriatal dopaminergic neurons form widely spread and highly dense axonal arborizations in the neostriatum. J Neurosci 29(2):444–453PubMedCrossRefGoogle Scholar
  36. 36.
    Matsuda W, Komatsu Y et al (2005) Levodopa treatment for patients in persistent vegetative or minimally conscious states. Neuropsychol Rehabil 15(3–4):414–427PubMedCrossRefGoogle Scholar
  37. 37.
    Matsuda W, Matsumura A et al (2003) Awakenings from persistent vegetative state: report of three cases with parkinsonism and brain stem lesions on MRI. J Neurol Neurosurg Psychiatry 74(11):1571–1573PubMedCrossRefGoogle Scholar
  38. 38.
    McGeer PL, McGeer EG et al (1977) Aging and extrapyramidal function. Arch Neurol 34(1):33–35PubMedCrossRefGoogle Scholar
  39. 39.
    Morrish PK, Rakshi JS et al (1998) Measuring the rate of progression and estimating the preclinical period of Parkinson’s disease with [18F]dopa PET. J Neurol Neurosurg Psychiatry 64(3):314–319PubMedCrossRefGoogle Scholar
  40. 40.
    Nakamura K, Matsumura K et al (2002) The rostral raphe pallidus nucleus mediates pyrogenic transmission from the preoptic area. J Neurosci 22(11):4600–4610PubMedGoogle Scholar
  41. 41.
    Nakamura K, Matsumura K et al (2004) Identification of sympathetic premotor neurons in medullary raphe regions mediating fever and other thermoregulatory functions. J Neurosci 24(23):5370–5380PubMedCrossRefGoogle Scholar
  42. 42.
    Nakamura Y, Nakamura K et al (2005) Direct pyrogenic input from prostaglandin EP3 receptor-expressing preoptic neurons to the dorsomedial hypothalamus. Eur J Neurosci 22(12):3137–3146PubMedCrossRefGoogle Scholar
  43. 43.
    Oorschot DE (1996) Total number of neurons in the neostriatal, pallidal, subthalamic, and substantia nigral nuclei of the rat basal ganglia: a stereological study using the cavalieri and optical disector methods. J Comp Neurol 366(4):580–599PubMedCrossRefGoogle Scholar
  44. 44.
    O’Sullivan SS, Evans AH et al (2009) Dopamine dysregulation syndrome: an overview of its epidemiology, mechanisms and management. CNS Drugs 23(2):157–170PubMedCrossRefGoogle Scholar
  45. 45.
    Prensa L, Parent A (2001) The nigrostriatal pathway in the rat: a single-axon study of the relationship between dorsal and ventral tier nigral neurons and the striosome/matrix striatal compartments. J Neurosci 21(18):7247–7260PubMedGoogle Scholar
  46. 46.
    Schultz W (1998) Predictive reward signal of dopamine neurons. J Neurophysiol 80(1):1–27PubMedGoogle Scholar
  47. 47.
    Sutton RS, Barto AG (1998) Reinforcement learning: an introduction. MIT Press, CambridgeGoogle Scholar
  48. 48.
    Trujillo KA, Kubota KS et al (2004) Continuous administration of opioids produces locomotor sensitization. Pharmacol Biochem Behav 79(4):661–669PubMedCrossRefGoogle Scholar
  49. 49.
    Wellstead P, Cloutier M (2011) An energy systems approach to Parkinson’s disease. Wiley Interdiscip Rev Syst Biol Med 3(1):1–6PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2012

Authors and Affiliations

  1. 1.Division of Anatomy and Cell Biology, Department of AnatomyShiga University of Medical ScienceOtsuJapan

Personalised recommendations