Skip to main content
SpringerLink
Log in

Plasticity of Neurons and Glia Following Neonatal Hypoxic-Ischemic Brain Injury in Rats

  • Original Paper
  • Published:
Neurochemical Research Aims and scope Submit manuscript

Abstract

Periventricular white matter injury in premature infants is linked to chronic neurological dysfunction. Periventricular white matter injury is caused by many mechanisms including hypoxia-ischemia (HI). Animal models of HI in the neonatal rodent brain can replicate some important features of periventricular white matter injury. Most rodent studies have focused upon early cellular and tissue events following unilateral neonatal HI that is elicited by unilateral carotid artery ligation and followed by timed exposure to moderate hypoxia. Milder hypoxic-ischemic insults elicit preferential white matter injury. Little information is available about long-term cellular effects of unilateral HI. One month after unilateral neonatal hypoxia ischemia, we show that all the components for structural reorganization of the brain are present in moderately injured rats. These components in the injured side include extensive influx of neurites, axonal and dendritic growth cones, abundant immature synapses, and myelination of many small axons. Surprisingly, this neural recovery is often found in and adjacent to cysts that have the ultrastructural features of bone extracellular matrix. In contrast, brains with severe hypoxia ischemia one month after injury still undergo massive neuronal degeneration. While massive destruction of neurons and glia are striking events shortly after brain HI, neural cells re-express their intrinsic properties and attempt an anatomical recovery long after injury.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7
Fig. 8

Similar content being viewed by others

References

  1. Rivkin MJ (1997). Hypoxic-ischemic brain injury in the term newborn. Neuropathology, clinical aspects, and neuroimaging. Clin Perinatol 24(3):607–625

    PubMed  CAS  Google Scholar 

  2. Hamrick SE, Miller SP, Leonard C et al (2004) Trends in severe brain injury and neurodevelopment outcome in premature newborn infants: the role of cystic periventricular leukomalacia. J Pediatr 145(5):593–599

    Article  PubMed  Google Scholar 

  3. Volpe JJ (2001) Perinatal brain injury: from pathogenesis to neuroprotection. Ment Retard Dev Disabil Res Rev 7(1):56–64

    Article  PubMed  CAS  Google Scholar 

  4. Rice JE III, Vannucci RC, Brierley JB (1981) The influence of immaturity on hypoxic-ischemic brain damage in the rat. Ann Neurol 9(2):131–141

    Article  PubMed  Google Scholar 

  5. Vannucci RC, Connor JR, Mauger DT et al (1999) Rat model of perinatal hypoxic-ischemic brain damage. J Neurosci Res 55(2):158–163

    Article  PubMed  CAS  Google Scholar 

  6. Hagberg H, Peebles D, Mallard C (2002) Models of white matter injury: comparison of infectious, hypoxic-ischemic, and excitotoxic insults. Ment Retard Dev Disabil Res Rev 8(1):30–38

    Article  PubMed  Google Scholar 

  7. Liu Y, Silverstein FS, Skoff R et al (2002) Hypoxic-ischemic oligodendroglial injury in neonatal rat brain. Pediatr Res 51(1):25–33

    PubMed  Google Scholar 

  8. Follett PL, Deng W, Dai W et al (2004) Glutamate receptor-mediated oligodendrocyte toxicity in periventricular leukomalacia: a protective role for topiramate. J Neurosci 24(18):4412–4420

    Article  PubMed  CAS  Google Scholar 

  9. Back SA, Han BH, Luo NL et al (2002) Selective vulnerability of late oligodendrocyte progenitors to hypoxia-ischemia. J Neurosci 22(2):455–463

    PubMed  CAS  Google Scholar 

  10. Fern R, Moller T (2000) Rapid ischemic cell death in immature oligodendrocytes: a fatal glutamate release feedback loop. J Neurosci 20(1):34–42

    PubMed  CAS  Google Scholar 

  11. Haynes RL, Baud O, Li J, Kinney HC et al (2005) Oxidative and nitrative injury in periventricular leukomalacia: a review. Brain Pathol 15(3):225–233

    Article  PubMed  CAS  Google Scholar 

  12. Back SA (2006) Perinatal white matter injury: the changing spectrum of pathology and emerging insights into pathogenetic mechanisms. Ment Retard Dev Disabil Res Rev 12(2):129–140

    Article  PubMed  Google Scholar 

  13. Skoff RP, Bessert DA, Barks JD et al (2001) Hypoxic-ischemic injury results in acute disruption of myelin gene expression and death of oligodendroglial precursors in neonatal mice. Int J Dev Neurosci 19(2):197–208

    Article  PubMed  CAS  Google Scholar 

  14. Levison SW, Rothstein RP, Romanko MJ et al (2001) Hypoxia/ischemia depletes the rat perinatal subventricular zone of oligodendrocyte progenitors and neural stem cells. Dev Neurosci 23(3):234–247

    Article  PubMed  CAS  Google Scholar 

  15. McQuillen PS, Sheldon RA, Shatz CJ et al (2003) Selective vulnerability of subplate neurons after early neonatal hypoxia-ischemia. J Neurosci 23(8):3308–3315

    PubMed  CAS  Google Scholar 

  16. Chun JJ, Shatz CJ (1988) A fibronectin-like molecule is present in the developing cat cerebral cortex and is correlated with subplate neurons. J Cell Biol 106(3):857–872

    Article  PubMed  CAS  Google Scholar 

  17. McLean C, Ferriero D (2004) Mechanisms of hypoxic-ischemic injury in the term infant. Semin Perinatol 28(6):425–432

    Article  PubMed  Google Scholar 

  18. Jansen EM, Low WC (1996) Long-term effects of neonatal ischemic-hypoxic brain injury on sensorimotor and locomotor tasks in rats. Behav Brain Res 78(2):189–194

    Article  PubMed  CAS  Google Scholar 

  19. Bona E, Johansson BB, Hagberg H (1997) Sensorimotor function and neuropathology five to six weeks after hypoxia-ischemia in seven-day-old rats. Pediatr Res 42(5):678–683

    PubMed  CAS  Google Scholar 

  20. Almli CR, Levy TJ, Han BH et al (2000) BDNF protects against spatial memory deficits following neonatal hypoxia-ischemia. Exp Neurol 2000 166(1):99–114

    Article  CAS  Google Scholar 

  21. Chou IC, Trakht T, Signori C et al (2001) Behavioral/environmental intervention improves learning after cerebral hypoxia-ischemia in rats. Stroke 32(9):2192–2197

    PubMed  CAS  Google Scholar 

  22. Ten VS, Wu EX, Tang H et al (2004) Late measures of brain injury after neonatal hypoxia-ischemia in mice. Stroke 35(9):2183–2188

    Article  PubMed  Google Scholar 

  23. Geddes R, Vannucci RC, Vannucci SJ (2001) Delayed cerebral atrophy following moderate hypoxia-ischemia in the immature rat. Dev Neurosci 23(3):180–185

    Article  PubMed  CAS  Google Scholar 

  24. Zaidi AU, Bessert DA, Ong JE et al (2004) New oligodendrocytes are generated after neonatal hypoxic-ischemic brain injury in rodents. Glia 46(4):380–390

    Article  PubMed  Google Scholar 

  25. Skoff RP, Ghandour MS, Knapp PE (1994) Postmitotic oligodendrocytes generated during postnatal cerebral development are derived from proliferation of immature oligodendrocytes. Glia 12(1):12–23

    Article  PubMed  CAS  Google Scholar 

  26. Schmued LC, Albertson C, Slikker W Jr (1997) Fluoro-Jade: a novel fluorochrome for the sensitive and reliable histochemical localization of neuronal degeneration. Brain Res 751(1):37–46

    Article  PubMed  CAS  Google Scholar 

  27. Skoff RP, Hamburger V (1974) Fine structure of dendritic and axonal growth cones in embryonic chick spinal cord. J Comp Neurol 153(2):107–147

    Article  PubMed  CAS  Google Scholar 

  28. Ichikawa M, Muramoto K, Kobayashi K et al (1993) Formation and maturation of synapses in primary cultures of rat cerebral cortical cells: an electron microscopic study. Neurosci Res 16(2):95–103

    Article  PubMed  CAS  Google Scholar 

  29. Shapiro LA, Ribak CE (2006) Newly born dentate granule neurons after pilocarpine-induced epilepsy have hilar basal dendrites with immature synapses. Epilepsy Res 69(1):53–66

    Article  PubMed  Google Scholar 

  30. Ross MH, Pawlina W (2006) Histology a text and atlas, 5th edn. Lippincott Williams & Wilkins Baltimore, MD Philadelphia PA

    Google Scholar 

  31. Bloom W, Fawcett DW (1997) A textbook of histology, 12th edn. Chapman and Hall, New York

    Google Scholar 

  32. Rhodin J (1974) Histology, Oxford University Press, New York, pp 185–203

    Google Scholar 

  33. Banker BQ, Larroche JC (1962) Periventricular leukomalacia of infancy. A form of neonatal anoxic encephalopathy. Arch Neurol 7:386–410

    PubMed  CAS  Google Scholar 

  34. Krageloh-Mann I, Toft P, Lunding J et al (1999) Brain lesions in preterms: origins, consequences and compensation. Acta Paediatr 88(8):897–908

    Article  PubMed  CAS  Google Scholar 

  35. Kubota T, Okumura A, Hayakawa F et al (2001) Relation between the date of cyst formation observable on ultrasonography and the timing of injury determined by serial electroencephalography in preterm infants with periventricular leukomalacia. Brain Dev 23(6):390–394

    Article  PubMed  CAS  Google Scholar 

  36. Pierrat V, Duquennoy C, van Haastert IC et al (2001) Ultrasound diagnosis and neurodevelopment outcome of localized and extensive cystic periventricular leucomalacia. Arch Dis Child Fetal Neonatal Ed 84(3):F151–F160

    Article  PubMed  CAS  Google Scholar 

  37. Tuor UI, Hudzik TJ, Malisza K et al (2001) Long-term deficits following cerebral hypoxia-ischemia in four-week-old rats: correspondence between behavioral, histological, and magnetic resonance imaging assessments. Exp Neurol 167(2):272–281

    Article  PubMed  CAS  Google Scholar 

  38. Klünemann HH, Ridha BH, Magy L et al (2005) The genetic causes of basal ganglia calcification, dementia, and bone cysts: DAP12 and TREM2. Neurology 64:1502–1507

    Article  PubMed  CAS  Google Scholar 

  39. Sizonenko SV, Kiss JZ, Inder T et al (2005) Distinctive neuropathologic alterations in the deep layers of the parietal cortex after moderate ischemic-hypoxic injury in the P3 immature rat brain. Pediatr Res 57(6):865–872

    Article  PubMed  CAS  Google Scholar 

  40. Cerghet M, Skoff RP, Bessert D et al (2006) Proliferation and death of oligodendrocytes and myelin proteins are differentially regulated in male and female rodents. J Neurosci 26(5):1439–1447

    Article  PubMed  CAS  Google Scholar 

  41. Weiss J, Takizawa B, McGee A et al (2004) Neonatal hypoxia suppresses oligodendrocyte Nogo-A and increases axonal sprouting in a rodent model for human prematurity. Exp Neurol 189(1):141–149

    Article  PubMed  CAS  Google Scholar 

  42. Fan L-W, Shuying L, Pang Y et al (2005) Hypoxia-ischemia induced neurological dysfunction and brain injury in the neonatal rat. Behav Brain Res 165(1):80–90

    Article  PubMed  CAS  Google Scholar 

  43. Holtmaat A, Wilbrecht L, Knott GW et al (2006) Experience-dependent and cell-type-specific spine growth in the neocortex. Nature 441(22):979–983

    Article  PubMed  CAS  Google Scholar 

  44. Ong J, Plane JM, Parent JM, Silverstein FS (2005) Hypoxic-ischemic injury stimulates subventricular zone proliferation and neurogenesis in the neonatal rat. Pediatr Res 58(3):600–606

    Article  PubMed  Google Scholar 

  45. Yang Z, Levison SW (2006) Hypoxia/ischemia expands the regenerative capacity of progenitors in the perinatal subventricular zone. Neuroscience 139(2):555–564

    Article  PubMed  CAS  Google Scholar 

  46. Giza CC, Prins ML (2006) Is being plastic fantastic? Mechanisms of altered plasticity after developmental brain injury. Dev Neuroscience (28):364–379

    Article  CAS  Google Scholar 

  47. Ment LR, Vohr B, Allan W et al (2003) Change in cognitive function over time in very low-birth-weight infants. JAMA 289(6):705–711

    Article  PubMed  Google Scholar 

Download references

Acknowledgments

This research was supported by NIH R21 NS40824 to FSS, JDEB, and RPS.

Author information

Authors and Affiliations

  1. Department of Anatomy and Cell Biology, Wayne State University School of Medicine, 540 E. Canfield, Detroit, MI, 48201, USA

    Robert P. Skoff & Denise Bessert

  2. Department of Pediatrics, University of Michigan, MSRB III, 48109-0646, Ann Arbor, MI, USA

    John D. E. Barks & Faye S. Silverstein

  3. Department of Neurology, University of Michigan, Ann Arbor, MI, USA

    Faye S. Silverstein

Authors
  1. Robert P. Skoff
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Denise Bessert
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. John D. E. Barks
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Faye S. Silverstein
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Robert P. Skoff.

Additional information

Special issue dedicated to Anthony Campagnoni.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Skoff, R.P., Bessert, D., Barks, J.D.E. et al. Plasticity of Neurons and Glia Following Neonatal Hypoxic-Ischemic Brain Injury in Rats. Neurochem Res 32, 331–342 (2007). https://doi.org/10.1007/s11064-006-9188-6

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11064-006-9188-6

Keywords

Search

Navigation