Neonatal hypoxia suppresses oligodendrocyte Nogo-A and increases axonal sprouting in a rodent model for human prematurity

Exp Neurol. 2004 Sep;189(1):141-9. doi: 10.1016/j.expneurol.2004.05.018.


Premature human infants frequently suffer from periventricular leukomalacia (PVL) characterized by the loss of central myelinated tracts in the brain [Neuropathology, 22 (2002) 193]. Rodent chronic sublethal hypoxia (CSH) from P3 to 33 (postnatal day 3-33) provides a model for PVL characterized by cerebral ventriculomegaly and reductions in cerebral white matter volume [Brain Res. Dev. Brain Res. 111 (1998) 197; Proc. Natl. Acad. Sci. USA 100 (2003) 11718]. Here, we demonstrate that mice exposed to CSH from P3 to P33 followed by normoxia from P33 to P75 continue to exhibit a locomotor hyperactivity that resembles behavioral changes observed in some human children with very low birth weights. Because periventricular white matter is specifically lost in PVL, we examined the expression of oligodendrocyte proteins. Hypoxic rearing dramatically decreases the level of the axon outgrowth inhibitor Nogo-A in oligodendrocytes of CNS white matter at P12. The Nogo-A decrease exceeds the moderate decrease in another myelin protein, myelin associated glycoprotein (MAG). Although myelin protein expression returns to normal by maturity (P75), persistent abnormalities in axonal trajectories are detectable. Anterograde axonal tracing from motor cortex demonstrates ectopic corticofugal fibers in the corticospinal tract (CST), corpus callosum, and caudate nucleus of adult animals reared in CSH. Thus, hypoxia-induced reduction in myelin-derived axon outgrowth inhibitors appears to contribute axonal misconnection to the pathology of very low birth weight infants.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Age Factors
  • Animals
  • Animals, Newborn
  • Axons / physiology*
  • Behavior, Animal
  • Biotin / analogs & derivatives*
  • Biotin / metabolism
  • Central Nervous System / anatomy & histology
  • Central Nervous System / metabolism
  • Central Nervous System / physiopathology
  • Dextrans / metabolism
  • Disease Models, Animal*
  • Exploratory Behavior / physiology
  • Humans
  • Hypoxia, Brain / pathology*
  • Hypoxia, Brain / physiopathology
  • Immunoblotting / methods
  • Immunohistochemistry / methods
  • Infant, Newborn
  • Infant, Premature / physiology*
  • Mice
  • Mice, Inbred C57BL
  • Myelin Basic Protein / metabolism
  • Myelin Proteins / metabolism*
  • Myelin-Associated Glycoprotein / metabolism
  • Nogo Proteins
  • Oligodendroglia / metabolism*
  • Receptors, Cell Surface / metabolism
  • Time Factors


  • Dextrans
  • Myelin Basic Protein
  • Myelin Proteins
  • Myelin-Associated Glycoprotein
  • Nogo Proteins
  • RTN4 protein, human
  • Receptors, Cell Surface
  • Rtn4 protein, mouse
  • biotinylated dextran amine
  • Biotin