Unmyelinated axon loss with postnatal hypertonia after fetal hypoxia

Alexander Drobyshevsky, Rugang Jiang, Laixiang Lin, Matthew Derrick, Kehuan Luo, Stephen A. Back, Sidhartha Tan

Research output: Contribution to journalArticle

20 Scopus citations

Abstract

Objective White matter (WM) injury due to myelination defects is believed to be responsible for the motor deficits seen in cerebral palsy. We tested the hypothesis that the predominant injury is to functional electrical connectivity in unmyelinated WM fibers by conducting a longitudinal study of central WM tracts in newborn rabbit kits with hypertonia in our model of cerebral palsy. Methods Pregnant rabbits at 70% gestation underwent 40-minute uterine ischemia. Motor deficits in newborn kits, including muscle hypertonia, were assessed by neurobehavioral testing. Major central WM tracts, including internal capsule, corpus callosum, anterior commissure, and fimbria hippocampi, were investigated for structural and functional injury using diffusion tensor magnetic resonance imaging (MRI), electrophysiological recordings of fiber conductivity in perfused brain slices, electron microscopy, and immunohistochemistry of oligodendrocyte lineage. Results Motor deficits were observed on postnatal day 1 (P1) when WM tracts were unmyelinated. Myelination occurred later and was obvious by P18. Hypertonia was associated with microstructural WM injury and unmyelinated axon loss at P1, diagnosed by diffusion tensor MRI and electron microscopy. Axonal conductivity from electrophysiological recordings in hypertonic P18 kits decreased only in unmyelinated fibers, despite a loss in both myelinated and unmyelinated axons. Interpretation Motor deficits in cerebral palsy were associated with loss of unmyelinated WM tracts. The contribution of injury to myelinated fibers that was observed at P18 is probably a secondary etiological factor in the motor and sensory deficits in the rabbit model of cerebral palsy. Ann Neurol 2014;75:533-541

Original languageEnglish (US)
Pages (from-to)533-541
Number of pages9
JournalAnnals of Neurology
Volume75
Issue number4
DOIs
StatePublished - Apr 2014

ASJC Scopus subject areas

  • Neurology
  • Clinical Neurology

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    Drobyshevsky, A., Jiang, R., Lin, L., Derrick, M., Luo, K., Back, S. A., & Tan, S. (2014). Unmyelinated axon loss with postnatal hypertonia after fetal hypoxia. Annals of Neurology, 75(4), 533-541. https://doi.org/10.1002/ana.24115