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The substantia nigra pars compacta of the Göttingen minipig: an anatomical and stereological study

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Abstract

Parkinson disease (PD) is a neurodegenerative disorder resulting from progressive loss of dopaminergic neurons in the substantia nigra pars compacta (SNc). Despite advances in medical and surgical therapies, many PD patients experience progression of their symptoms and medical side effects over time. To explore new treatments, new animal models mimicking the progressive PD nature are needed. The pig is well suited for this purpose with its large gyrated brain, sensitive to the neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). The objective of this study was to provide the anatomical foundation for such a model, describing in detail the SNc in normal Göttingen minipigs and estimating the volume and total number of tyrosine hydroxylase (TH)-positive neurons. The brain stems of 6 Göttingen minipigs were paraffin embedded and serially cut before Nissl staining and immunohistochemical visualization of TH. The volume of the SNc and the total number of TH-positive neurons were estimated by design-based stereology. The substantia nigra was located at the dorsal rim of the crus cerebri extending throughout the mesencephalon. A dorsal pars compacta and a ventral pars reticulata were demonstrated. The SNc merged with the ventral tegmental area medially and the retro-rubral field dorsocaudolaterally. The total number of TH-positive neurons in the SNc unilaterally was estimated to 80,700 [74,100;87,300], and the volume estimate was 26.4 mm3 [25.0;27.8]. We conclude that the anatomy of the SNc in the Göttingen minipig corresponds well with that of higher primates, and is well suited for further studies aimed at optimizing this non-primate large animal model for PD.

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References

  • Bjarkam CR, Sørensen JC (2006) Progress and development in Parkinson disease therapy. In: Rattan S, Kassem M (eds) Prevention and treatment of age-related diseases, chap 3. Springer, Berlin. ISBN 1-4020-4884-X

  • Bjarkam CR, Sørensen JC, Geneser FA, Sunde N, Østergaard K (2001) New strategies for the treatment of Parkinson’s disease holds considerable promise for the future management of neurodegenerative disorders. Biogerontology 2:193–207

    Article  PubMed  CAS  Google Scholar 

  • Bjarkam CR, Cancian G, Larsen M, Rosendal F, Ettrup KS, Zeidler D, Blankholm AD, Ostergaard L, NAa Sunde, Sorensen JC (2004) A MRI-compatible stereotaxic localizer box enables high-precision stereotaxic procedures in pigs. J Neurosci Methods 139:293–298. doi:10.1016/j.jneumeth.2004.05.004

    Article  PubMed  CAS  Google Scholar 

  • Bjarkam CR, Larsen M, Watanabe H, Röhl L, Simonsen CZ, Pedersen M, Ringgaard S, Andersen F, Cumming P, Dalmose AL, Møller A, Jensen LW, Danielsen EH, Dalmau I, Finsen B, Oettingen Gv, Gjedde A, Sørensen JC (2005) A porcine model of subthalamic high-frequency deep brain stimulation in Parkinson’s disease. In: Willow MJ (ed) Parkinson’s disease: new research, chap 5. Nova Science Publishers, New York, pp 99–119. ISBN-1-59454-352-6

  • Bjarkam CR, Jørgensen RL, Jensen KN, Sunde NA, Sorensen JC (2008a) Deep brain stimulation electrode anchoring using BioGlue®, a protective electrode covering, and a titanium microplate. J Neurosci Methods 168:151–155. doi:10.1016/j.jneumeth.2007.09.008

    Article  PubMed  CAS  Google Scholar 

  • Bjarkam CR, Nielsen MS, Glud AN, Rosendal F, Mogensen P, Bender D, Møller A, Sorensen JC (2008b) Neuromodulation in a minipig MPTP model of Parkinson disease. Br J Neurosurg 22(Suppl 1):S9–S12. doi:10.1080/02688690802448285

    Article  PubMed  Google Scholar 

  • Bové J, Prou D, Perier C, Przedborski S (2005) Toxin-induced models of Parkinson’s disease. NeuroRx 2:484–494

    Article  PubMed  Google Scholar 

  • Burns RS, Chiueh CC, Markey SP, Ebert MH, Jacobowitz DM, Kopin IJ (1983) A primate model of parkinsonism: selective destruction of dopaminergic neurons in the pars compacta of the substantia nigra by N-methyl-4-phenyl-1, 2, 3, 6-tetrahydropyridine. Proc Natl Acad Sci USA 80:4546–4550

    Article  PubMed  CAS  Google Scholar 

  • Dall AM, Danielsen EH, Sørensen JC, Andersen F, Møller A, Zimmer J, Gjedde AH, Group TheDaNeX, Cumming P (2002) Quantitative [18F]Fluorodopa/PET and histology of fetal mesencephalic dopaminergic grafts to the striatum of MPTP-poisoned minipigs. Cell Transplant 11:733–746

    PubMed  Google Scholar 

  • Dalmose AL, Bjarkam CR, Sørensen JC, Djurhuus JC, Jørgensen TM (2004) Effects of high frequency deep brain stimulation on urine storage and voiding function in conscious minipigs. Neurourol Urodyn 23:265–272. doi:10.1002/nau.20026

    Article  PubMed  CAS  Google Scholar 

  • Dalmose AL, Bjarkam CR, Djurhuus JC (2005) Stereotactic electrical stimulation of the pontine micturition centre in the pig. BJU Int 95:886–889. doi:10.1111/j.1464-410X.2005.05421.x

    Article  PubMed  Google Scholar 

  • Danielsen EH, Cumming P, Andersen F, Bender D, Brevig T, Falborg L, Gee A, Gillings NM, Hansen SB, Hermansen F, Johansen J, Johansen TE, Dahl-Jørgensen A, Jørgensen HA, Meyer M, Munk O, Pedersen EB, Poulsen PH, Rodell AB, Sakoh M, Simonsen CZ, Smith DF, Sørensen JC, Østergaard L, Zimmer J, Gjedde A, Møller A (2000) The DaNeX study of embryonic mesencephalic, dopaminergic tissue grafted to a minipig model of Parkinson’s disease: preliminary findings of effect of MPTP poisoning on striatal dopaminergic markers. Cell Transplant 9:247–259

    PubMed  CAS  Google Scholar 

  • Felix B, Leger ME, Albe-Fessard D, Marcilloux JC, Rampin O, Laplace JP (1999) Stereotaxic atlas of the pig brain. Brain Res Bull 49:1–139

    Article  PubMed  CAS  Google Scholar 

  • Goodman S, Check E (2002) The great primate debate. Nature 417:684–687. doi:10.1111/j.1464-410X.2005.05421.x

    Article  PubMed  CAS  Google Scholar 

  • Hardman CD, Henderson JM, Finkelstein DI, Horne MK, Paxinos G, Halliday GM (2002) Comparison of the basal ganglia in rats, marmosets, macaques, baboons, and humans: volume and neuron number for the output, internal relay, and striatal modulating nuclei. J Comp Neurol 445:238–255

    Article  PubMed  Google Scholar 

  • Janson AM, Møller A (1993) Chronic nicotine treatment counteracts nigral cell loss induced by a partial mesodiencephalic hemitransection: An analysis of the total number and mean volume of neurons and glia in substantia nigra of the male rat. Neuroscience 57(4):931–941

    Article  PubMed  CAS  Google Scholar 

  • Jenner P (2008) Functional models of Parkinson’s disease: a valuable tool in the development of novel therapies. Ann Neurol 64(Suppl):S16–S29. doi:10.1002/ana.21489

    PubMed  CAS  Google Scholar 

  • Jensen KN, Deding D, Sørensen JC, Bjarkam CR (2009) Long-term implantation of deep brain stimulation electrodes in the pontine micturition center of the Göttingen minipig. Acta Neurochir. doi:10.1007/s00701-009-0334-1

  • Kirik D, Annett LE, Burger C, Muzyczka N, Mandel RJ, Björklund A (2003) Nigrostriatal alpha-synucleinopathy induced by viral vector-mediated overexpression of human alpha-synuclein: a new primate model of Parkinson’s disease. Proc Natl Acad Sci USA 100(5):2884–2889. doi:10.1073/pnas.0536383100

    Article  PubMed  CAS  Google Scholar 

  • Koller WC, Cersosimo MG (2004) Neuroprotection in Parkinson’s disease: an elusive goal. Curr Neurol Neurosci Rep 4:277–283

    Article  PubMed  Google Scholar 

  • Krack P, Batir A, Blercom NV, Chabardes S, Fraix V, Ardouin C, Koudsie A, Limousin PD, Benazzouz A, LeBas JF, Benabid AL, Pollak P (2003) Five-year follow-up of bilateral stimulation of the subthalamic nucleus in advanced Parkinson’s disease. N Engl J Med 349(20):1925–1934. doi:10.1056/NEJMoa035275

    Article  PubMed  CAS  Google Scholar 

  • Lambertsen KL, Meldgaard M, Ladeby R, Finsen B (2005) A quantitative study of microglial-macrophage synthesis of tumor necrosis factor during acute and late focal cerebral ischemia in mice. J Cereb Blood Flow Metab 25:119–135. doi:10.1038/sj.jcbfm.9600014

    Article  PubMed  CAS  Google Scholar 

  • Larsen M, Bjarkam CR, Østergaard K, West MJ, Sørensen JC (2004) The anatomy of the porcine subthalamic nucleus evaluated with immunohistochemistry and design-based stereology. Anat Embryol 208(3):239–247. doi:10.1007/s00429-004-0395-0

    Article  PubMed  Google Scholar 

  • Lind NM, Moustgaard A, Jelsing J, Vajta G, Cumming P, Hansen AK (2007) The use of pigs in neuroscience: modeling brain disorders. Neurosci Biobehav Rev 31:728–751. doi:10.1016/j.neubiorev.2007.02.003

    Article  PubMed  CAS  Google Scholar 

  • Lindvall O, Wahlberg LU (2008) Encapsulated cell biodelivery of GDNF: a novel clinical strategy for neuroprotection and neuroregeneration in Parkinson’s disease? Exp Neurol 209:82–88. doi:10.1016/j.expneurol.2007.08.019

    Article  PubMed  CAS  Google Scholar 

  • Litvan I, Chesselet M-F, Gasser T, Di Monte DA, Parker D Jr, Hagg T, Hardy J, Jenner P, Myers RH, Price D, Hallett M, Langston WJ, Lang AE, Halliday G, Rocca W, Duyckaerts C, Dickson DW, Ben-Shlomo Y, Goetz CG, Melamed E (2007) The etiopathogenesis of Parkinson disease and suggestions for future research. Part II. J Neuropath Exp Neurol 66(5):329–336. doi:10.1097/nen.0b013e318053716a Duyckaerts C

    Article  PubMed  CAS  Google Scholar 

  • Mikkelsen M, Møller A, Jensen LH, Pedersen A, Harajehi JB, Pakkenberg H (1999) MPTP-induced parkinsonism in minipigs: a behavioral, biochemical, and histological study. Neurotoxicol Teratol 21:169–175

    Article  PubMed  CAS  Google Scholar 

  • Müller GJ, Møller A, Johansen FF (2001) Stereological cell counts of GABAergic neurons in rat dentate hilus following transient cerebral ischemia. Exp Brain Res 141:380–388. doi:10.1007/s002210100879

    Article  PubMed  Google Scholar 

  • 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 366:580–599. doi:10.1002/(SICI)1096-9861(19960318)366:4<580:AID-CNE3>3.0.CO;2-0

    Article  PubMed  CAS  Google Scholar 

  • Østergaard K, Aa Sunde N (2006) Evolution of Parkinson’s disease during 4 years of bilateral deep brain stimulation of the subthalamic nucleus. Mov Disord 21(5):624–631. doi:10.1002/mds.20776

    Article  PubMed  Google Scholar 

  • Østergaard K, Holm IE, Zimmer J (1992) Tyrosine hydroxylase and acetylcholinesterase in the domestic pig mesencephalon: an immunocytochemical and histochemical study. J Comp Neurol 322:149–166. doi:10.1002/cne.903220202

    Article  PubMed  Google Scholar 

  • Pakkenberg B, Møller A, Gundersen HJG, Mouritzen Dam A, Pakkenberg H (1991) 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. J Neurol Neurosurg Psychiatry 54:30–33

    Article  PubMed  CAS  Google Scholar 

  • Pakkenberg H, Andersen BB, Burns RS, Pakkenberg B (1995) A stereological study of substantia nigra in young and old rhesus monkeys. Brain Res 693:201–206

    Article  PubMed  CAS  Google Scholar 

  • Rosendal F, Pedersen M, Sangill R, Stødkilde-Jørgensen H, Nielsen MS, Bjarkam CR, Sunde N, Sørensen JC (2009) MRI protocol for in vivo visualization of the Göttingen minipig brain improves targeting in experimental functional neurosurgery. Brain Res Bull 79:41–45. doi:10.1016/j.brainresbull.2009.01.002

    Article  PubMed  Google Scholar 

  • Rudow G, O’Brian R, Savonenko AV, Resnick SM, Zonderman AB, Pletnikova O, Marsh L, Dawson TM, Crain BJ, West MJ, Troncoso JC (2008) Morphometry of the human substantia nigra in ageing and Parkinson’s disease. Acta Neuropathol 115:461–470. doi:10.1007/s00401-008-0352-8

    Article  PubMed  Google Scholar 

  • Solnitzky O (1939) The hypothalamus and subthalamus of Sus Scrofa. J Comp Neurol 70:191–229

    Article  Google Scholar 

  • Sørensen JC, Bjarkam CR, Danielsen EH, Simonsen CZ, Geneser FA (2000) Oriented sectioning of irregular tissue blocks in relation to computerized scanning modalities: results from the domestic pig brain. J Neurosci Methods 104(1):93–98

    Article  Google Scholar 

  • Watanabe H, Andersen F, Simonsen CZ, Evans SM, Gjedde A, Cumming P (2001) MR-based statistical atlas of the Göttingen minipig brain. Neuroimage 14:1089–1096. doi:10.1006/nimg.2001.0910

    Article  PubMed  CAS  Google Scholar 

  • West MJ (1999) Stereological methods for estimating the total number of neurons and synapses: issues of precision and bias. Trends Neurosci 22:51–61

    Article  PubMed  CAS  Google Scholar 

  • West MJ, Slomianka L, Gundersen HJ (1991) Unbiased stereological estimation of the total number of neurons in the subdivisions of the rat hippocampus using the optical fractionator. Anat Rec 231:482–497. doi:10.1002/ar.1092310411

    Article  PubMed  CAS  Google Scholar 

  • West MJ, Bach G, Søderman A, Jensen JL (2008) Synaptic contact number and size in stratum radiatum CA1 of APP/PS1ΔE9 transgenic mice. Neurobiol Aging. doi:10.1016/j.neurobiolaging.2008.01.009

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Acknowledgments

We acknowledge with gratitude the skillful assistance of Ms A. Funder, Ms D. Jensen, Ms L. Munkøe, Mr A. Meier and the staff at Paaskehøjgaard Animal Care Facility. We greatly acknowledge the financial support of The Danish Medical Association/Svend Aage Nielsen Wacherhausen’s Foundation, The Helga and Peter Korning Foundation, The Karen Elise Jensen Foundation, The Lundbeck Foundation, and the Danish Medical Research Council.

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  1. Faculty of Health Sciences, Institute of Anatomy, University of Aarhus, 8000, Århus C, Denmark

    Mette Slot Nielsen & Carsten Reidies Bjarkam

  2. Department of Neurosurgery, Aarhus University Hospital, 8000, Århus C, Denmark

    Jens Christian Sørensen & Carsten Reidies Bjarkam

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  1. Mette Slot Nielsen
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  2. Jens Christian Sørensen
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  3. Carsten Reidies Bjarkam
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Correspondence to Mette Slot Nielsen.

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Nielsen, M.S., Sørensen, J.C. & Bjarkam, C.R. The substantia nigra pars compacta of the Göttingen minipig: an anatomical and stereological study. Brain Struct Funct 213, 481–488 (2009). https://doi.org/10.1007/s00429-009-0217-5

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