The substantia nigra of the human brain. I. Nigrosomes and the nigral matrix, a compartmental organization based on calbindin D(28K) immunohistochemistry.

Parkinson's disease is characterized by massive degeneration of dopamine-containing neurons in the midbrain. However, the vulnerability of these neurons is heterogeneous both across different midbrain dopamine-containing cell groups and within the substantia nigra, the brain structure most affected in this disease. To determine the exact pattern of cell loss and to map the cellular distribution of candidate pathogenic molecules, it is necessary to have landmarks independent of the degenerative process by which to subdivide the substantia nigra. We have developed a protocol for this purpose based on immunostaining for calbindin D(28K), a protein present in striatonigral afferent fibres. We used it to examine post-mortem brain samples from seven subjects who had had no history of neurological or psychiatric disease. We found intense immunostaining for calbindin D(28K) associated with the neuropil of the ventral midbrain. Within the calbindin-positive region, there were conspicuous calbindin-poor zones. Analysed in serial sections, many of the calbindin-poor zones seen in individual sections were continuous with one another, forming elements of larger, branched three-dimensional structures. Sixty per cent of all dopamine-containing neurons in the substantia nigra pars compacta were located within the calbindin-rich zone, which we named the nigral matrix, and 40% were packed together within the calbindin-poor zones, which we named nigrosomes. We identified five different nigrosomes. This organization was consistent from one control brain to another. We propose that subdivision of the human substantia nigra based on patterns of calbindin immunostaining provides a key tool for analysing the organization of the substantia nigra and offers a new approach to analysing molecular expression patterns in the substantia nigra and the specific patterns of nigral cell degeneration in Parkinson's disease.

[1]  Wade K. Smith,et al.  Midbrain dopaminergic cell loss in parkinson's disease: Computer visualization , 1989, Annals of neurology.

[2]  Jérôme Yelnik,et al.  A histological atlas of the macaque (Macaca, mulatta) substantia nigra in ventricular coordinates , 1985, Brain Research Bulletin.

[3]  P. Emson,et al.  Calbindin D28K as a marker for the degeneration of the striatonigral pathway in Huntington's disease , 1990, Brain Research.

[4]  G. Halliday,et al.  Quantitative analysis of the variability of substantia nigra pigmented cell clusters in the human , 1995, Neuroscience.

[5]  C D Marsden,et al.  Differing patterns of striatal 18F‐dopa uptake in Parkinson's disease, multiple system atrophy, and progressive supranuclear palsy , 1990, Annals of neurology.

[6]  Robert L. Nussbaum,et al.  Mutation in the α-Synuclein Gene Identified in Families with Parkinson's Disease , 1997 .

[7]  A. Parent,et al.  The subcortical afferents to caudate nucleus and putamen in primate: A fluorescence retrograde double labeling study , 1983, Neuroscience.

[8]  W. Gibb,et al.  Melanin, tyrosine hydroxylase, calbindin and substance P in the human midbrain and substantia nigra in relation to nigrostriatal projections and differential neuronal susceptibility in Parkinson's disease , 1992, Brain Research.

[9]  H J Gundersen,et al.  The absolute number of nerve cells in substantia nigra in normal subjects and in patients with Parkinson's disease estimated with an unbiased stereological method. , 1991, Journal of neurology, neurosurgery, and psychiatry.

[10]  S. Kish,et al.  Uneven pattern of dopamine loss in the striatum of patients with idiopathic Parkinson's disease. Pathophysiologic and clinical implications. , 1988, The New England journal of medicine.

[11]  A. Graybiel,et al.  Subdivisions of the dopamine-containing A8-A9-A10 complex identified by their differential mesostriatal innervation of striosomes and extrastriosomal matrix , 1987, Neuroscience.

[12]  JM Tepper,et al.  GABAA receptor-mediated inhibition of rat substantia nigra dopaminergic neurons by pars reticulata projection neurons , 1995, The Journal of neuroscience : the official journal of the Society for Neuroscience.

[13]  W. Gibb,et al.  Anatomy, pigmentation, ventral and dorsal subpopulations of the substantia nigra, and differential cell death in Parkinson's disease. , 1991, Journal of neurology, neurosurgery, and psychiatry.

[14]  J. Hedreen,et al.  Organization of striatopallidal, striatonigral, and nigrostriatal projections in the macaque , 1991, The Journal of comparative neurology.

[15]  S. Minoshima,et al.  Mutations in the parkin gene cause autosomal recessive juvenile parkinsonism , 1998, Nature.

[16]  S H Snyder,et al.  Positron emission tomographic imaging of the dopamine transporter with 11C‐WIN 35,428 reveals marked declines in mild Parkinson's disease , 1993, Annals of neurology.

[17]  P. Mcgeer,et al.  Aging and extrapyramidal function. , 1977, Archives of neurology.

[18]  A. Lees,et al.  Ageing and Parkinson's disease: substantia nigra regional selectivity. , 1991, Brain : a journal of neurology.

[19]  Y. Agid,et al.  Do parkinsonian symptoms and levodopa‐induced dyskinesias start in the foot? , 1994, Neurology.

[20]  A. Graybiel,et al.  Distinct nigrostriatal projection systems innervate striosomes and matrix in the primate striatum , 1989, Brain Research.

[21]  A. Graybiel,et al.  Differences in tyrosine hydroxylase-like immunoreactivity characterize the mesostriatal innervation of striosomes and extrastriosomal matrix at maturity. , 1987, Proceedings of the National Academy of Sciences of the United States of America.

[22]  A. Graybiel,et al.  Melanized dopaminergic neurons are differentially susceptible to degeneration in Parkinson's disease , 1988, Nature.

[23]  Dr. Peter Henricus Maria Franciscus van Domburg,et al.  The Human Substantia Nigra and Ventral Tegmental Area , 1991, Advances in Anatomy Embryology and Cell Biology.

[24]  P. V. Domburg,et al.  The Human Substantia Nigra and Ventral Tegmental Area: A Neuroanatomical Study With Notes on Aging and Aging Diseases , 1991 .

[25]  P. Yates,et al.  Dopaminergic neurotransmitter systems in Alzheimer's disease and in Down's syndrome at middle age. , 1987, Journal of neurology, neurosurgery, and psychiatry.

[26]  S. Goto,et al.  Calbindin‐D28K in the basal ganglia of patients with parkinsonism , 1992, Annals of neurology.

[27]  B. Konigsmark,et al.  Methods for counting neurons , 1970 .

[28]  J. Szabo.  Organization of the ascending striatal afferents in monkeys , 1980, The Journal of comparative neurology.

[29]  H. Braak,et al.  Nuclear configuration and neuronal types of the nucleus niger in the brain of the human adult. , 1986, Human neurobiology.

[30]  M. Abercrombie.  Estimation of nuclear population from microtome sections , 1946, The Anatomical record.

[31]  Walle J. H. Nauta,et al.  Contemporary Research Methods in Neuroanatomy , 1970, Springer Berlin Heidelberg.

[32]  C. W. Ragsdale,et al.  Histochemically distinct compartments in the striatum of human, monkeys, and cat demonstrated by acetylthiocholinesterase staining. , 1978, Proceedings of the National Academy of Sciences of the United States of America.

[33]  E. Abercrombie,et al.  Amphetamine‐induced release of dendritic dopamine in substantia nigra pars reticulata: D1‐mediated behavioral and electrophysiological effects , 1996, Synapse.

[34]  A. Graybiel,et al.  The substantia nigra of the human brain. II. Patterns of loss of dopamine-containing neurons in Parkinson's disease. , 1999, Brain : a journal of neurology.