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In Vivo Neurochemical Characterization of Developing Guinea Pigs and the Effect of Chronic Fetal Hypoxia

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Abstract

The guinea pig is a frequently used animal model for human pregnancy complications, such as oxygen deprivation or hypoxia, which result in altered brain development. To investigate the impact of in utero chronic hypoxia on brain development, pregnant guinea pigs underwent either normoxic or hypoxic conditions at about 70 % of 65-day term gestation. After delivery, neurochemical profiles consisting of 19 metabolites and macromolecules were obtained from the neonatal cortex, hippocampus, and striatum from birth to 12 weeks postpartum using in vivo 1H MR spectroscopy at 9.4 T. The effects of chronic fetal hypoxia on the neurochemical profiles were particularly significant at birth. However, the overall developmental trends of neurochemical concentration changes were similar between normoxic and hypoxic animals. Alterations of neurochemicals including N-acetylaspartate (NAA), phosphorylethanolamine, creatine, phosphocreatine, and myo-inositol indicate neuronal loss, delayed myelination, and altered brain energetics due to chronic fetal hypoxia. These observed neurochemical alterations in the developing brain may provide insights into hypoxia-induced brain pathology, neurodevelopmental compromise, and potential neuroprotective measures.

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References

  1. Grafe MR (1994) The correlation of prenatal brain damage with placental pathology. J Neuropathol Exp Neurol 53:407–415

    Article  CAS  PubMed  Google Scholar 

  2. Rees S, Harding R, Walker D (2008) An adverse intrauterine environment: implications for injury and altered development of the brain. Int J Dev Neurosci 26:3–11

    Article  PubMed  Google Scholar 

  3. Rees S, Harding R, Walker D (2011) The biological basis of injury and neuroprotection in the fetal and neonatal brain. Int J Dev Neurosci 29:551–563

    Article  PubMed  PubMed Central  Google Scholar 

  4. Salihagic-Kadic A, Medic M, Jugovic D, Kos M, Latin V, Kusan Jukic M, Arbeille P (2006) Fetal cerebrovascular response to chronic hypoxia—implications for the prevention of brain damage. J Matern Fetal Neonatal Med 19:387–396

    Article  PubMed  Google Scholar 

  5. Shankaran S, Laptook AR, Ehrenkranz RA, Tyson JE, McDonald SA, Donovan EF, Fanaroff AA, Poole WK, Wright LL, Higgins RD, Finer NN, Carlo WA, Duara S, Oh W, Cotten CM, Stevenson DK, Stoll BJ, Lemons JA, Guillet R, Jobe AH (2005) Whole-body hypothermia for neonates with hypoxic-ischemic encephalopathy. N Engl J Med 353:1574–1584

    Article  CAS  PubMed  Google Scholar 

  6. Rees S, Breen S, Loeliger M, McCrabb G, Harding R (1999) Hypoxemia near mid-gestation has long-term effects on fetal brain development. J Neuropathol Exp Neurol 58:932–945

    Article  CAS  PubMed  Google Scholar 

  7. Loeliger M, Watson CS, Reynolds JD, Penning DH, Harding R, Bocking AD, Rees SM (2003) Extracellular glutamate levels and neuropathology in cerebral white matter following repeated umbilical cord occlusion in the near term fetal sheep. Neuroscience 116:705–714

    Article  CAS  PubMed  Google Scholar 

  8. Kim J, Choi IY, Dong Y, Wang WT, Brooks WM, Weiner CP, Lee P (2015) Chronic fetal hypoxia affects axonal maturation in guinea pigs during development: a longitudinal diffusion tensor imaging and T2 mapping study. J Magn Reson Imaging 42:658–665

    Article  PubMed  Google Scholar 

  9. Nitsos I, Rees S (1990) The effects of intrauterine growth retardation on the development of neuroglia in fetal guinea pigs. An immunohistochemical and an ultrastructural study. Int J Dev Neurosci 8:233–244

    Article  CAS  PubMed  Google Scholar 

  10. Mallard EC, Rehn A, Rees S, Tolcos M, Copolov D (1999) Ventriculomegaly and reduced hippocampal volume following intrauterine growth-restriction: implications for the aetiology of schizophrenia. Schizophr Res 40:11–21

    Article  CAS  PubMed  Google Scholar 

  11. Rees S, Bocking AD, Harding R (1988) Structure of the fetal sheep brain in experimental growth retardation. J Dev Physiol 10:211–225

    CAS  PubMed  Google Scholar 

  12. Conn PM (2013) Animal models for the study of human disease. Elsevier, London; Waltham, MA

    Google Scholar 

  13. Pappas JJ, Petropoulos S, Suderman M, Iqbal M, Moisiadis V, Turecki G, Matthews SG, Szyf M (2014) The multidrug resistance 1 gene Abcb1 in brain and placenta: comparative analysis in human and guinea pig. PLoS One 9:e111135

    Article  PubMed  PubMed Central  Google Scholar 

  14. Thompson LP, Aguan K, Pinkas G, Weiner CP (2000) Chronic hypoxia increases the NO contribution of acetylcholine vasodilation of the fetal guinea pig heart. Am J Physiol Regul Integr Comp Physiol 279:R1813–R1820

    CAS  PubMed  Google Scholar 

  15. Agrawal HC, Davis JM, Himwich WA (1968) Changes in some free amino acids of guinea pig brain during postnatal ontogeny. J Neurochem 15:529–531

    Article  CAS  PubMed  Google Scholar 

  16. Dong Y, Yu Z, Sun Y, Zhou H, Stites J, Newell K, Weiner CP (2011) Chronic fetal hypoxia produces selective brain injury associated with altered nitric oxide synthases. Am J Obstet Gynecol 204:26

    Article  Google Scholar 

  17. Schuff N, Matsumoto S, Kmiecik J, Studholme C, Du A, Ezekiel F, Miller BL, Kramer JH, Jagust WJ, Chui HC, Weiner MW (2009) Cerebral blood flow in ischemic vascular dementia and Alzheimer’s disease, measured by arterial spin-labeling magnetic resonance imaging. Alzheimers Dement 5:454–462

    Article  PubMed  PubMed Central  Google Scholar 

  18. Dobbing J, Sands J (1970) Growth and development of the brain and spinal cord of the guinea pig. Brain Res 17:115–123

    Article  CAS  PubMed  Google Scholar 

  19. Oja SS, Uusitalo AJ, Vahvelainen ML, Piha RS (1968) Changes in cerebral and hepatic amino acids in the rat and guinea pig during development. Brain Res 11:655–661

    Article  CAS  PubMed  Google Scholar 

  20. Sheltawy A, Dawson RMC (1969) The deposition and metabolism of polyphosphoinositides in rat and guinea-pig brain during development. Biochem J 111:147−154

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Tkac I, Starcuk Z, Choi IY, Gruetter R (1999) In vivo H-1 NMR spectroscopy of rat brain at 1 ms echo time. Magn Reson Med 41:649–656

    Article  CAS  PubMed  Google Scholar 

  22. Gruetter R, Tkac I (2000) Field mapping without reference scan using asymmetric echo-planar techniques. Magn Reson Med 43:319–323

    Article  CAS  PubMed  Google Scholar 

  23. Provencher SW (1993) Estimation of metabolite concentrations from localized in-vivo proton NMR-spectra. Magn Reson Med 30:672–679

    Article  CAS  PubMed  Google Scholar 

  24. Golda V (1995) Water and electrolyte content of the rat brain: age and strain dependence. Homeost Health Dis 36:238–239

    Google Scholar 

  25. Yamagata K, Takahashi KP, Ohnishi R, Kawakami K, Kageyama K (1983) Quick gas-chromatographic method for measuring the water-content of brain-tissue—with reference to age-related-changes of rat neocortex. Brain Dev 5:582–584

    Article  CAS  PubMed  Google Scholar 

  26. Graves J, Himwich HE (1955) Age and the water content of rabbit brain parts. Am J Physiol 180:205–208

    CAS  PubMed  Google Scholar 

  27. Tkac I, Rao R, Georgieff MK, Gruetter R (2003) Developmental and regional changes in the neurochemical profile of the rat brain determined by in vivo H-1 NMR spectroscopy. Magn Reson Med 50:24–32

    Article  CAS  PubMed  Google Scholar 

  28. Loose MD, Terasawa E (1985) Pulsatile infusion of luteinizing hormone-releasing hormone induces precocious puberty (vaginal opening and first ovulation) in the immature female guinea pig. Biol Reprod 33:1084–1093

    Article  CAS  PubMed  Google Scholar 

  29. Bluml S, Wisnowski JL, Nelson MD Jr, Paquette L, Gilles FH, Kinney HC, Panigrahy A (2013) Metabolic maturation of the human brain from birth through adolescence: insights from in vivo magnetic resonance spectroscopy. Cereb Cortex 23:2944–2955

    Article  PubMed  Google Scholar 

  30. Kreis R, Ernst T, Ross BD (1993) Development of the human brain: in vivo quantification of metabolite and water content with proton magnetic resonance spectroscopy. Magn Reson Med 30:424–437

    Article  CAS  PubMed  Google Scholar 

  31. Koundal S, Gandhi S, Kaur T, Khushu S (2014) Neurometabolic and structural alterations in rat brain due to acute hypobaric hypoxia: in vivo 1H MRS at 7 T. NMR Biomed 27:341–347

    Article  CAS  PubMed  Google Scholar 

  32. Ottersen OP, Zhang N, Walberg F (1992) Metabolic compartmentation of glutamate and glutamine: morphological evidence obtained by quantitative immunocytochemistry in rat cerebellum. Neuroscience 46:519–534

    Article  CAS  PubMed  Google Scholar 

  33. Kaiser LG, Schuff N, Cashdollar N, Weiner MW (2005) Age-related glutamate and glutamine concentration changes in normal human brain: 1H MR spectroscopy study at 4 T. Neurobiol Aging 26:665–672

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Baslow MH (2003) N-acetylaspartate in the vertebrate brain: metabolism and function. Neurochem Res 28:941–953

    Article  CAS  PubMed  Google Scholar 

  35. Raman L, Tkac I, Ennis K, Georgieff MK, Gruetter R, Rao R (2005) In vivo effect of chronic hypoxia on the neurochemical profile of the developing rat hippocampus. Brain Res Dev Brain Res 156:202–209

    Article  CAS  PubMed  Google Scholar 

  36. Clark JB (1998) N-acetyl aspartate: a marker for neuronal loss or mitochondrial dysfunction. Dev Neurosci 20(4–5):271–276

    Article  CAS  PubMed  Google Scholar 

  37. Kirmani BF, Jacobowitz DM, Kallarakal AT, Namboodiri MA (2002) Aspartoacylase is restricted primarily to myelin synthesizing cells in the CNS: therapeutic implications for Canavan disease. Brain Res Mol Brain Res 107:176–182

    Article  CAS  PubMed  Google Scholar 

  38. Milev P, Miranowski S, Lim KO (2009) Magnetic resonance spectroscopy. In: Javitt DC, Lajtha A, Kantrowitz J (eds) Handbook of neurochemistry and molecular neurobiology: schizophrenia, vol 3. Springer, Berlin, p 549

    Google Scholar 

  39. Yager JY, Brucklacher RM, Vannucci RC (1992) Cerebral energy metabolism during hypoxia-ischemia and early recovery in immature rats. Am J Physiol 262:H672–H677

    CAS  PubMed  Google Scholar 

  40. Munns SE, Meloni BP, Knuckey NW, Arthur PG (2003) Primary cortical neuronal cultures reduce cellular energy utilization during anoxic energy deprivation. J Neurochem 87:764–772

    Article  CAS  PubMed  Google Scholar 

  41. Bluml S, Seymour KJ, Ross BD (1999) Developmental changes in choline- and ethanolamine-containing compounds measured with proton-decoupled P-31 MRS in in vivo human brain. Magn Reson Med 42:643–654

    Article  CAS  PubMed  Google Scholar 

  42. Pettegrew JW, Panchalingam K, Withers G, McKeag D, Strychor S (1990) Changes in brain energy and phospholipid metabolism during development and aging in the Fischer 344 rat. J Neuropathol Exp Neurol 49:237–249

    Article  CAS  PubMed  Google Scholar 

  43. Kinoshita Y, Yokota A, Koga Y (1994) Phosphorylethanolamine content of human brain tumors. Neurol Med Chir 34:803–806

    Article  CAS  Google Scholar 

  44. Langmeier M, Pokorny J, Mares J, Mares P, Trojan S (1987) Effect of prolonged hypobaric hypoxia during postnatal development on myelination of the corpus callosum in rats. J Hirnforsch 28:385–395

    CAS  PubMed  Google Scholar 

  45. Ment LR, Schwartz M, Makuch RW, Stewart WB (1998) Association of chronic sublethal hypoxia with ventriculomegaly in the developing rat brain. Brain Res Dev Brain Res 111:197–203

    Article  CAS  PubMed  Google Scholar 

  46. Chugani HT (1998) A critical period of brain development: studies of cerebral glucose utilization with PET. Prev Med 27:184–188

    Article  CAS  PubMed  Google Scholar 

  47. Harik SI, Behmand RA, LaManna JC (1994) Hypoxia increases glucose transport at blood-brain barrier in rats. J Appl Physiol 77:896–901

    CAS  PubMed  Google Scholar 

  48. Pouwels PJ, Frahm J (1998) Regional metabolite concentrations in human brain as determined by quantitative localized proton MRS. Magn Reson Med 39:53–60

    Article  CAS  PubMed  Google Scholar 

  49. van Zijl PC, Barker PB (1997) Magnetic resonance spectroscopy and spectroscopic imaging for the study of brain metabolism. Ann N Y Acad Sci 820:75–96

    Article  PubMed  Google Scholar 

  50. Hofmann L, Slotboom J, Jung B, Maloca P, Boesch C, Kreis R (2002) Quantitative 1H-magnetic resonance spectroscopy of human brain: influence of composition and parameterization of the basis set in linear combination model-fitting. Magn Reson Med 48:440–453

    Article  CAS  PubMed  Google Scholar 

  51. Gruetter R, Garwood M, Ugurbil K, Seaquist ER (1996) Observation of resolved glucose signals in 1H NMR spectra of the human brain at 4 Tesla. Magn Reson Med 36:1–6

    Article  CAS  PubMed  Google Scholar 

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Acknowledgments

This study was partly supported by the Public Health Service (R01 HL049041-13; CPW), Centers for Disease Control and Prevention (DP00187-5; CPW), and the National Institute of Child Health and Human Development (R03 HD062734; YD). The Hoglund Brain Imaging Center is supported by a generous gift from Forrest and Sally Hoglund and funding from the National Institutes of Health (P30 HD002528).

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Authors and Affiliations

  1. Hoglund Brain Imaging Center, University of Kansas Medical Center, 3901 Rainbow Boulevard, MSN 1052, Kansas City, KS, 66160, USA

    Wen-Tung Wang, Phil Lee, Jieun Kim, William M. Brooks & In-Young Choi

  2. The Department of Molecular and Integrative Physiology, University of Kansas Medical Center, Kansas City, KS, 66160, USA

    Phil Lee & In-Young Choi

  3. The Department of Obstetrics and Gynecology, University of Kansas Medical Center, Kansas City, KS, 66160, USA

    Yafeng Dong & Carl P. Weiner

  4. The Department of Biostatistics, University of Kansas Medical Center, Kansas City, KS, 66160, USA

    Hung-Wen Yeh

  5. The Department of Neurology, University of Kansas Medical Center, Kansas City, KS, 66160, USA

    William M. Brooks & In-Young Choi

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  1. Wen-Tung Wang
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Correspondence to In-Young Choi.

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This article is a part of 40th Year of Neurochemical Research Special issue (Neurochem Res (2016) 41:1–2).

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Wang, WT., Lee, P., Dong, Y. et al. In Vivo Neurochemical Characterization of Developing Guinea Pigs and the Effect of Chronic Fetal Hypoxia. Neurochem Res 41, 1831–1843 (2016). https://doi.org/10.1007/s11064-016-1924-y

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  • DOI: https://doi.org/10.1007/s11064-016-1924-y

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