Cellular and Molecular Neurobiology

, Volume 33, Issue 8, pp 1087–1098 | Cite as

Short-Term Cuprizone Feeding Induces Selective Amino Acid Deprivation with Concomitant Activation of an Integrated Stress Response in Oligodendrocytes

  • Johannes Goldberg
  • Moritz Daniel
  • Yasemin van Heuvel
  • Marion Victor
  • Cordian Beyer
  • Tim Clarner
  • Markus Kipp
Original Research

Abstract

Cuprizone [bis(cyclohexylidenehydrazide)]-induced toxic demyelination is an experimental approach frequently used to study de- and re-myelination in the central nervous system. In this model, mice are fed with the copper chelator cuprizone which leads to oligodendrocyte apoptosis and subsequent microgliosis, astrocytosis, and demyelination. The underlying mechanisms of cuprizone-induced oligodendrocyte death are still unknown. We analysed differences in amino acid levels after short-term cuprizone exposure (i.e., 4 days). Furthermore, an amino acid response (AAR) pathway activated in oligodendrocytes after cuprizone intoxication was evaluated. Short-term cuprizone exposure resulted in a selective decrease of alanine, glycine, and proline plasma levels, which was paralleled by an increase of apoptotic cells in the liver and a decrease of alanine aminotransferase in the serum. These parameters were paralleled by oligodendrocyte apoptosis and the induction of an AAR with increased expression of the transcription factors ATF-3 and ATF-4 (activating transcription factor-3 and -4). Immunohistochemistry revealed that ATF-3 is exclusively expressed by oligodendrocytes and localized to the nuclear compartment. Our results suggest that cuprizone-induced liver dysfunction results in amino acid starvation and in consequence to the activation of an AAR. We propose that this stress response modulates oligodendrocyte viability in the cuprizone animal model.

Keywords

Integrated stress response ATF3 Cuprizone Amino acid 

References

  1. Acs P, Kalman B (2012) Pathogenesis of multiple sclerosis: what can we learn from the cuprizone model. Methods Mol Biol 900:403–431. doi:10.1007/978-1-60761-720-4_20 PubMedCrossRefGoogle Scholar
  2. Acs P, Komoly S (2012) Selective ultrastructural vulnerability in the cuprizone-induced experimental demyelination. Ideggyogy Sz 65(7–8):266–270PubMedGoogle Scholar
  3. Acs P, Kipp M, Norkute A, Johann S, Clarner T, Braun A, Berente Z, Komoly S, Beyer C (2009) 17beta-estradiol and progesterone prevent cuprizone provoked demyelination of corpus callosum in male mice. Glia 57(8):807–814PubMedCrossRefGoogle Scholar
  4. Belachew S, Malgrange B, Rigo JM, Rogister B, Leprince P, Hans G, Nguyen L, Moonen G (2000) Glycine triggers an intracellular calcium influx in oligodendrocyte progenitor cells which is mediated by the activation of both the ionotropic glycine receptor and Na+-dependent transporters. Eur J Neurosci 12(6):1924–1930PubMedCrossRefGoogle Scholar
  5. Benetti F, Ventura M, Salmini B, Ceola S, Carbonera D, Mammi S, Zitolo A, D’Angelo P, Urso E, Maffia M, Salvato B, Spisni E (2010) Cuprizone neurotoxicity, copper deficiency and neurodegeneration. Neurotoxicology 31(5):509–517. doi:10.1016/j.neuro.2010.05.008 PubMedCrossRefGoogle Scholar
  6. Bertfield DL, Jumma O, Pitceathly RD, Sussman JD (2008) Copper deficiency: an unusual case of myelopathy with neuropathy. Ann Clin Biochem 45(Pt 4):434–435. doi:10.1258/acb.2008.007218 PubMedCrossRefGoogle Scholar
  7. Bhat NR, Zhang P, Bhat AN (1995) The expression of myristoylated alanine-rich C-kinase substrate in oligodendrocytes is developmentally regulated. Dev Neurosci 17(4):256–263PubMedCrossRefGoogle Scholar
  8. Blakemore WF (1972) Observations on oligodendrocyte degeneration, the resolution of status spongiosus and remyelination in cuprizone intoxication in mice. J Neurocytol 1(4):413–426PubMedCrossRefGoogle Scholar
  9. Blakemore WF (1973) Demyelination of the superior cerebellar peduncle in the mouse induced by cuprizone. J Neurol Sci 20(1):63–72PubMedCrossRefGoogle Scholar
  10. Braun A, Dang J, Johann S, Beyer C, Kipp M (2009) Selective regulation of growth factor expression in cultured cortical astrocytes by neuro-pathological toxins. Neurochem Int 55(7):610–618PubMedCrossRefGoogle Scholar
  11. Bruck W, Pfortner R, Pham T, Zhang J, Hayardeny L, Piryatinsky V, Hanisch UK, Regen T, van Rossum D, Brakelmann L, Hagemeier K, Kuhlmann T, Stadelmann C, John GR, Kramann N, Wegner C (2012) Reduced astrocytic NF-kappaB activation by laquinimod protects from cuprizone-induced demyelination. Acta Neuropathol. doi:10.1007/s00401-012-1009-1 Google Scholar
  12. Buschmann JP, Berger K, Awad H, Clarner T, Beyer C, Kipp M (2012) Inflammatory response and chemokine expression in the white matter corpus callosum and gray matter cortex region during cuprizone-induced demyelination. J Mol Neurosci 48(1):66–76. doi:10.1007/s12031-012-9773-x PubMedCrossRefGoogle Scholar
  13. Carlton WW (1966) Response of mice to the chelating agents sodium diethyldithiocarbamate, alpha-benzoinoxime, and biscyclohexanone oxaldihydrazone. Toxicol Appl Pharmacol 8(3):512–521PubMedCrossRefGoogle Scholar
  14. Carlton WW (1967) Studies on the induction of hydrocephalus and spongy degeneration by cuprizone feeding and attempts to antidote the toxicity. Life Sci 6(1):11–19PubMedCrossRefGoogle Scholar
  15. Chang Y, An DH, Xing Y, Qi X (2012) Central pontine and extrapontine myelinolysis associated with acute hepatic dysfunction. Neurol Sci 33(3):673–676. doi:10.1007/s10072-011-0838-3 PubMedCrossRefGoogle Scholar
  16. Clarner T, Diederichs F, Berger K, Denecke B, Gan L, van der Valk P, Beyer C, Amor S, Kipp M (2012) Myelin debris regulates inflammatory responses in an experimental demyelination animal model and multiple sclerosis lesions. Glia. doi:10.1002/glia.22367 Google Scholar
  17. De AK, Subramanian M (1982) Effect of cuprizone feeding on hepatic superoxide dismutase and cytochrome oxidase activities in mice. Experientia 38(7):784–785PubMedCrossRefGoogle Scholar
  18. Ferreira D, Castro S, Nadais G, Dias Costa JM, Fonseca JM (2011) Demyelinating lesions with features of Balo’s concentric sclerosis in a patient with active hepatitis C and human herpesvirus 6 infection. Eur J Neurol 18(1):e6–7. doi:10.1111/j.1468-1331.2010.03201.x PubMedCrossRefGoogle Scholar
  19. Fletcher JM, Lalor SJ, Sweeney CM, Tubridy N, Mills KH (2010) T cells in multiple sclerosis and experimental autoimmune encephalomyelitis. Clin Exp Immunol 162(1):1–11PubMedCrossRefGoogle Scholar
  20. Fu L, Kilberg MS (2013) Elevated cJUN expression and an ATF/CRE site within the ATF3 promoter contribute to activation of ATF3 transcription by the amino acid response. Physiol Genomics 45(4):127–137. doi:10.1152/physiolgenomics.00160.2012 PubMedCrossRefGoogle Scholar
  21. Goodman BP, Chong BW, Patel AC, Fletcher GP, Smith BE (2006) Copper deficiency myeloneuropathy resembling B12 deficiency: partial resolution of MR imaging findings with copper supplementation. AJNR Am J Neuroradiol 27(10):2112–2114PubMedGoogle Scholar
  22. Gudi V, Skuljec J, Yildiz O, Frichert K, Skripuletz T, Moharregh-Khiabani D, Voss E, Wissel K, Wolter S, Stangel M (2011) Spatial and temporal profiles of growth factor expression during CNS demyelination reveal the dynamics of repair priming. PLoS ONE 6(7):e22623. doi:10.1371/journal.pone.0022623 PubMedCrossRefGoogle Scholar
  23. Harding BN, Alsanjari N, Smith SJ, Wiles CM, Thrush D, Miller DH, Scaravilli F, Harding AE (1995) Progressive neuronal degeneration of childhood with liver disease (Alpers’ disease) presenting in young adults. J Neurol Neurosurg Psychiatry 58(3):320–325PubMedCrossRefGoogle Scholar
  24. Hesse A, Wagner M, Held J, Bruck W, Salinas-Riester G, Hao Z, Waisman A, Kuhlmann T (2010) In toxic demyelination oligodendroglial cell death occurs early and is FAS independent. Neurobiol Dis 37(2):362–369. doi:10.1016/j.nbd.2009.10.016 PubMedCrossRefGoogle Scholar
  25. Hoppel CL, Tandler B (1973) Biochemical effects of cuprizone on mouse liver and heart mitochondria. Biochem Pharmacol 22(18):2311–2318PubMedCrossRefGoogle Scholar
  26. Hussain R, Ghoumari AM, Bielecki B, Steibel J, Boehm N, Liere P, Macklin WB, Kumar N, Habert R, Mhaouty-Kodja S, Tronche F, Sitruk-Ware R, Schumacher M, Ghandour MS (2013) The neural androgen receptor: a therapeutic target for myelin repair in chronic demyelination. Brain 136(Pt 1):132–146. doi:10.1093/brain/aws284 PubMedGoogle Scholar
  27. Illig T, Gieger C, Zhai G, Romisch-Margl W, Wang-Sattler R, Prehn C, Altmaier E, Kastenmuller G, Kato BS, Mewes HW, Meitinger T, de Angelis MH, Kronenberg F, Soranzo N, Wichmann HE, Spector TD, Adamski J, Suhre K (2010) A genome-wide perspective of genetic variation in human metabolism. Nat Genet 42(2):137–141. doi:10.1038/ng.507 PubMedCrossRefGoogle Scholar
  28. Jourdan C, Petersen AK, Gieger C, Doring A, Illig T, Wang-Sattler R, Meisinger C, Peters A, Adamski J, Prehn C, Suhre K, Altmaier E, Kastenmuller G, Romisch-Margl W, Theis FJ, Krumsiek J, Wichmann HE, Linseisen J (2012) Body fat free mass is associated with the serum metabolite profile in a population-based study. PLoS ONE 7(6):e40009. doi:10.1371/journal.pone.0040009 PubMedCrossRefGoogle Scholar
  29. Kamei A, Ichinohe S, Onuma R, Hiraga S, Fujiwara T (1997) Acute disseminated demyelination due to primary human herpesvirus-6 infection. Eur J Pediatr 156(9):709–712PubMedCrossRefGoogle Scholar
  30. Kang Z, Liu L, Spangler R, Spear C, Wang C, Gulen MF, Veenstra M, Ouyang W, Ransohoff RM, Li X (2012) IL-17-induced Act1-mediated signaling is critical for cuprizone-induced demyelination. J Neurosci 32(24):8284–8292. doi:10.1523/JNEUROSCI.0841-12.2012 PubMedCrossRefGoogle Scholar
  31. Kesterson JW, Carlton WW (1971) Histopathologic and enzyme histochemical observations of the cuprizone-induced brain edema. Exp Mol Pathol 15(1):82–96PubMedCrossRefGoogle Scholar
  32. Kilberg MS, Shan J, Su N (2009) ATF4-dependent transcription mediates signaling of amino acid limitation. Trends Endocrinol Metab 20(9):436–443. doi:10.1016/j.tem.2009.05.008 PubMedCrossRefGoogle Scholar
  33. Kilberg MS, Balasubramanian M, Fu L, Shan J (2012) The transcription factor network associated with the amino acid response in mammalian cells. Adv Nutr 3(3):295–306. doi:10.3945/an.112.001891 PubMedCrossRefGoogle Scholar
  34. Kipp M, Clarner T, Dang J, Copray S, Beyer C (2009) The cuprizone animal model: new insights into an old story. Acta Neuropathol 118(6):723–736. doi:10.1007/s00401-009-0591-3 PubMedCrossRefGoogle Scholar
  35. Kipp M, Gingele S, Pott F, Clarner T, van der Valk P, Denecke B, Gan L, Siffrin V, Zipp F, Dreher W, Baumgartner W, Pfeifenbring S, Godbout R, Amor S, Beyer C (2011a) BLBP-expression in astrocytes during experimental demyelination and in human multiple sclerosis lesions. Brain Behav Immun 25(8):1554–1568. doi:10.1016/j.bbi.2011.05.003 PubMedCrossRefGoogle Scholar
  36. Kipp M, Norkus A, Krauspe B, Clarner T, Berger K, van der Valk P, Amor S, Beyer C (2011b) The hippocampal fimbria of cuprizone-treated animals as a structure for studying neuroprotection in multiple sclerosis. Inflamm Res 60(8):723–726. doi:10.1007/s00011-011-0339-0 PubMedCrossRefGoogle Scholar
  37. Kipp M, van der Valk P, Amor S (2012) Pathology of multiple sclerosis. CNS Neurol Disord Drug Targets 11(5):506–517PubMedCrossRefGoogle Scholar
  38. Kiryu-Seo S, Ohno N, Kidd GJ, Komuro H, Trapp BD (2010) Demyelination increases axonal stationary mitochondrial size and the speed of axonal mitochondrial transport. J Neurosci 30(19):6658–6666. doi:10.1523/JNEUROSCI.5265-09.2010 PubMedCrossRefGoogle Scholar
  39. Komoly S, Jeyasingham MD, Pratt OE, Lantos PL (1987) Decrease in oligodendrocyte carbonic anhydrase activity preceding myelin degeneration in cuprizone induced demyelination. J Neurol Sci 79(1–2):141–148PubMedCrossRefGoogle Scholar
  40. Kumar N, Gross JB Jr, Ahlskog JE (2004) Copper deficiency myelopathy produces a clinical picture like subacute combined degeneration. Neurology 63(1):33–39PubMedCrossRefGoogle Scholar
  41. Kumar G, Goyal MK, Lucchese S, Dhand U (2011) Copper deficiency myelopathy can also involve the brain stem. AJNR Am J Neuroradiol 32(1):E14–15. doi:10.3174/ajnr.A2261 PubMedGoogle Scholar
  42. Liu G, Su L, Hao X, Zhong N, Zhong D, Singhal S, Liu X (2012) Salermide up-regulates death receptor 5 expression through the ATF4-ATF3-CHOP axis and leads to apoptosis in human cancer cells. J Cell Mol Med 16(7):1618–1628. doi:10.1111/j.1582-4934.2011.01401.x PubMedCrossRefGoogle Scholar
  43. Lovas G, Nielsen JA, Johnson KR, Hudson LD (2010) Alterations in neuronal gene expression profiles in response to experimental demyelination and axonal transection. Mult Scler 16(3):303–316. doi:10.1177/1352458509357063 PubMedCrossRefGoogle Scholar
  44. Ludwin SK (1978) Central nervous system demyelination and remyelination in the mouse: an ultrastructural study of cuprizone toxicity. Lab Investig 39(6):597–612PubMedGoogle Scholar
  45. Lv D, Meng D, Zou FF, Fan L, Zhang P, Yu Y, Fang J (2011) Activating transcription factor 3 regulates survivability and migration of vascular smooth muscle cells. IUBMB Life 63(1):62–69. doi:10.1002/iub.416 PubMedCrossRefGoogle Scholar
  46. Marik C, Felts PA, Bauer J, Lassmann H, Smith KJ (2007) Lesion genesis in a subset of patients with multiple sclerosis: a role for innate immunity? Brain 130(Pt 11):2800–2815PubMedCrossRefGoogle Scholar
  47. Matsushima GK, Morell P (2001) The neurotoxicant, cuprizone, as a model to study demyelination and remyelination in the central nervous system. Brain Pathol 11(1):107–116PubMedCrossRefGoogle Scholar
  48. McFarland HF, Martin R (2007) Multiple sclerosis: a complicated picture of autoimmunity. Nat Immunol 8(9):913–919PubMedCrossRefGoogle Scholar
  49. Messori L, Casini A, Gabbiani C, Sorace L, Muniz-Miranda M, Zatta P (2007) Unravelling the chemical nature of copper cuprizone. Dalton Trans 21:2112–2114. doi:10.1039/b701896g PubMedCrossRefGoogle Scholar
  50. Min Y, Park SH, Hwang SB (2012) Corticospinal tract and pontocerebellar fiber of central pontine myelinolysis. Ann Rehabil Med 36(6):887–892. doi:10.5535/arm.2012.36.6.887 PubMedCrossRefGoogle Scholar
  51. Montejo Gonzalez JC, Mesejo A, Bonet Saris A (2011) Guidelines for specialized nutritional and metabolic support in the critically-ill patient: update. Consensus SEMICYUC-SENPE: liver failure and liver transplantation. Nutr Hosp 26(Suppl 2):27–31. doi:10.1590/S0212-16112011000800006 PubMedGoogle Scholar
  52. Nielsen JA, Maric D, Lau P, Barker JL, Hudson LD (2006) Identification of a novel oligodendrocyte cell adhesion protein using gene expression profiling. J Neurosci 26(39):9881–9891. doi:10.1523/JNEUROSCI.2246-06.2006 PubMedCrossRefGoogle Scholar
  53. Pan YX, Chen H, Thiaville MM, Kilberg MS (2007) Activation of the ATF3 gene through a co-ordinated amino acid-sensing response programme that controls transcriptional regulation of responsive genes following amino acid limitation. Biochem J 401(1):299–307. doi:10.1042/BJ20061261 PubMedCrossRefGoogle Scholar
  54. Petronilli V, Zoratti M (1990) A characterization of cuprizone-induced giant mouse liver mitochondria. J Bioenerg Biomembr 22(5):663–677PubMedCrossRefGoogle Scholar
  55. Pott F, Gingele S, Clarner T, Dang J, Baumgartner W, Beyer C, Kipp M (2009) Cuprizone effect on myelination, astrogliosis and microglia attraction in the mouse basal ganglia. Brain Res 1305:137–149. doi:10.1016/j.brainres.2009.09.084 PubMedCrossRefGoogle Scholar
  56. Russanov EM, Ljutakova SG (1980) Effect of cuprizone on copper exchange and superoxide dismutase activity in rat liver. Gen Pharmacol 11(6):535–538PubMedCrossRefGoogle Scholar
  57. Sayers CM, Papandreou I, Guttmann DM, Maas NL, Diehl JA, Witze ES, Koong AC, Koumenis C (2013) Identification and characterization of a potent activator of p53-independent cellular senescence via a small-molecule screen for modifiers of the integrated stress response. Mol Pharmacol 83(3):594–604. doi:10.1124/mol.112.081810 PubMedCrossRefGoogle Scholar
  58. Sellner J, Kraus J, Awad A, Milo R, Hemmer B, Stuve O (2011) The increasing incidence and prevalence of female multiple sclerosis—a critical analysis of potential environmental factors. Autoimmun Rev 10(8):495–502PubMedCrossRefGoogle Scholar
  59. Sikalidis AK, Lee JI, Stipanuk MH (2011) Gene expression and integrated stress response in HepG2/C3A cells cultured in amino acid deficient medium. Amino Acids 41(1):159–171. doi:10.1007/s00726-010-0571-x PubMedCrossRefGoogle Scholar
  60. Siskova Z, Baron W, de Vries H, Hoekstra D (2006) Fibronectin impedes “myelin” sheet-directed flow in oligodendrocytes: a role for a beta 1 integrin-mediated PKC signaling pathway in vesicular trafficking. Mol Cell Neurosci 33(2):150–159. doi:10.1016/j.mcn.2006.07.001 PubMedCrossRefGoogle Scholar
  61. Skripuletz T, Gudi V, Hackstette D, Stangel M (2011) De- and remyelination in the CNS white and grey matter induced by cuprizone: the old, the new, and the unexpected. Histol Histopathol 26(12):1585–1597PubMedGoogle Scholar
  62. Song DY, Oh KM, Yu HN, Park CR, Woo RS, Jung SS, Baik TK (2011) Role of activating transcription factor 3 in ischemic penumbra region following transient middle cerebral artery occlusion and reperfusion injury. Neurosci Res 70(4):428–434. doi:10.1016/j.neures.2011.05.002 PubMedCrossRefGoogle Scholar
  63. Sookoian S, Pirola CJ (2012) Alanine and aspartate aminotransferase and glutamine-cycling pathway: their roles in pathogenesis of metabolic syndrome. World J Gastroenterol 18(29):3775–3781. doi:10.3748/wjg.v18.i29.3775 PubMedCrossRefGoogle Scholar
  64. Southwood CM, Garbern J, Jiang W, Gow A (2002) The unfolded protein response modulates disease severity in Pelizaeus–Merzbacher disease. Neuron 36(4):585–596PubMedCrossRefGoogle Scholar
  65. Suhre K, Shin SY, Petersen AK, Mohney RP, Meredith D, Wagele B, Altmaier E, Deloukas P, Erdmann J, Grundberg E, Hammond CJ, de Angelis MH, Kastenmuller G, Kottgen A, Kronenberg F, Mangino M, Meisinger C, Meitinger T, Mewes HW, Milburn MV, Prehn C, Raffler J, Ried JS, Romisch-Margl W, Samani NJ, Small KS, Wichmann HE, Zhai G, Illig T, Spector TD, Adamski J, Soranzo N, Gieger C (2011) Human metabolic individuality in biomedical and pharmaceutical research. Nature 477(7362):54–60. doi:10.1038/nature10354 PubMedCrossRefGoogle Scholar
  66. Suzuki K (1969) Giant hepatic mitochondria: production in mice fed with cuprizone. Science 163(3862):81–82PubMedCrossRefGoogle Scholar
  67. Suzuki K, Kikkawa Y (1969) Status spongiosus of CNS and hepatic changes induced by cuprizone (biscyclohexanone oxalyldihydrazone). Am J Pathol 54(2):307–325PubMedGoogle Scholar
  68. Utku U, Asil T, Balci K, Uzunca I, Celik Y (2005) Hepatic myelopathy with spastic paraparesis. Clin Neurol Neurosurg 107(6):514–516. doi:10.1016/j.clineuro.2004.10.002 PubMedCrossRefGoogle Scholar
  69. van der Star BJ, Vogel DY, Kipp M, Puentes F, Baker D, Amor S (2012) In vitro and in vivo models of multiple sclerosis. CNS Neurol Disord Drug Targets 11(5):570–588PubMedCrossRefGoogle Scholar
  70. Venturini G (1973) Enzymic activities and sodium, potassium and copper concentrations in mouse brain and liver after cuprizone treatment in vivo. J Neurochem 21(5):1147–1151PubMedCrossRefGoogle Scholar
  71. Yoon K, Lee SO, Cho SD, Kim K, Khan S, Safe S (2011) Activation of nuclear TR3 (NR4A1) by a diindolylmethane analog induces apoptosis and proapoptotic genes in pancreatic cancer cells and tumors. Carcinogenesis 32(6):836–842. doi:10.1093/carcin/bgr040 PubMedCrossRefGoogle Scholar
  72. Yoshizawa F (2012) New therapeutic strategy for amino acid medicine: notable functions of branched chain amino acids as biological regulators. J Pharmacol Sci 118(2):149–155PubMedCrossRefGoogle Scholar
  73. Zeng H, Saari JT, Johnson WT (2007) Copper deficiency decreases complex IV but not complex I, II, III, or V in the mitochondrial respiratory chain in rat heart. J Nutr 137(1):14–18PubMedGoogle Scholar
  74. Zhang SJ, Buchthal B, Lau D, Hayer S, Dick O, Schwaninger M, Veltkamp R, Zou M, Weiss U, Bading H (2011) A signaling cascade of nuclear calcium-CREB-ATF3 activated by synaptic NMDA receptors defines a gene repression module that protects against extrasynaptic NMDA receptor-induced neuronal cell death and ischemic brain damage. J Neurosci 31(13):4978–4990. doi:10.1523/JNEUROSCI.2672-10.2011 PubMedCrossRefGoogle Scholar
  75. Zou LP, Pelidou SH, Abbas N, Deretzi G, Mix E, Schaltzbeerg M, Winblad B, Zhu J (1999) Dynamics of production of MIP-1alpha, MCP-1 and MIP-2 and potential role of neutralization of these chemokines in the regulation of immune responses during experimental autoimmune neuritis in Lewis rats. J Neuroimmunol 98(2):168–175PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2013

Authors and Affiliations

  • Johannes Goldberg
    • 1
  • Moritz Daniel
    • 1
  • Yasemin van Heuvel
    • 1
  • Marion Victor
    • 1
  • Cordian Beyer
    • 1
  • Tim Clarner
    • 1
  • Markus Kipp
    • 1
  1. 1.Faculty of Medicine, Institute of NeuroanatomyRWTH Aachen UniversityAachenGermany

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