title: Abbreviated exposure to hypoxia is sufficient to induce CNS dysmyelination, modulate spinal motor neuron composition, and impair motor development in neonatal mice.
abstract: Neonatal white matter injury (nWMI) is an increasingly common cause of cerebral palsy that results predominantly from hypoxic injury to progenitor cells including those of the oligodendrocyte lineage. Existing mouse models of nWMI utilize prolonged periods of hypoxia during the neonatal period, require complex cross-fostering and exhibit poor growth and high mortality rates. Abnormal CNS myelin composition serves as the major explanation for persistent neuro-motor deficits. Here we developed a simplified model of nWMI with low mortality rates and improved growth without cross-fostering. Neonatal mice are exposed to low oxygen from postnatal day (P) 3 to P7, which roughly corresponds to the period of human brain development between gestational weeks 32 and 36. CNS hypomyelination is detectable for 2-3 weeks post injury and strongly correlates with levels of body and brain weight loss. Immediately following hypoxia treatment, cell death was evident in multiple brain regions, most notably in superficial and deep cortical layers as well as the subventricular zone progenitor compartment. PDGFαR, Nkx2.2, and Olig2 positive oligodendrocyte progenitor cell were significantly reduced until postnatal day 27. In addition to CNS dysmyelination we identified a novel pathological marker for adult hypoxic animals that strongly correlates with life-long neuro-motor deficits. Mice reared under hypoxia reveal an abnormal spinal neuron composition with increased small and medium diameter axons and decreased large diameter axons in thoracic lateral and anterior funiculi. Differences were particularly pronounced in white matter motor tracts left and right of the anterior median fissure. Our findings suggest that 4 days of exposure to hypoxia are sufficient to induce experimental nWMI in CD1 mice, thus providing a model to test new therapeutics. Pathological hallmarks of this model include early cell death, decreased OPCs and hypomyelination in early postnatal life, followed by dysmyelination, abnormal spinal neuron composition, and neuro-motor deficits in adulthood.
authors.affiliation: Department of Neurology, Mayo Clinic College of Medicine, Rochester, Minnesota, United States of America.
authors.forename: Jens O
authors.initials: JO
authors.lastname: Watzlawik
authors.affiliation: Department of Neurology, Mayo Clinic College of Medicine, Rochester, Minnesota, United States of America; Department of Pediatric and Adolescent Medicine, Mayo Clinic College of Medicine, Rochester, Minnesota, United States of America.
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Kahoud
authors.affiliation: Children's Health Research Center, Sanford Research, Sioux Falls, South Dakota, United States of America.
authors.forename: Ryan J
authors.initials: RJ
authors.lastname: O'Toole
authors.affiliation: Children's Health Research Center, Sanford Research, Sioux Falls, South Dakota, United States of America.
authors.forename: Katherine A M
authors.initials: KA
authors.lastname: White
authors.affiliation: Children's Health Research Center, Sanford Research, Sioux Falls, South Dakota, United States of America.
authors.forename: Alyssa R
authors.initials: AR
authors.lastname: Ogden
authors.affiliation: Department of Neurology, Mayo Clinic College of Medicine, Rochester, Minnesota, United States of America.
authors.forename: Meghan M
authors.initials: MM
authors.lastname: Painter
authors.affiliation: Department of Neurology, Mayo Clinic College of Medicine, Rochester, Minnesota, United States of America.
authors.forename: Bharath
authors.initials: B
authors.lastname: Wootla
authors.affiliation: Department of Neurology, Mayo Clinic College of Medicine, Rochester, Minnesota, United States of America.
authors.forename: Louisa M
authors.initials: LM
authors.lastname: Papke
authors.affiliation: Department of Neurology, Mayo Clinic College of Medicine, Rochester, Minnesota, United States of America.
authors.forename: Aleksandar
authors.initials: A
authors.lastname: Denic
authors.affiliation: Children's Health Research Center, Sanford Research, Sioux Falls, South Dakota, United States of America.
authors.forename: Jill M
authors.initials: JM
authors.lastname: Weimer
authors.affiliation: Department of Pediatric and Adolescent Medicine, Mayo Clinic College of Medicine, Rochester, Minnesota, United States of America.
authors.forename: William A
authors.initials: WA
authors.lastname: Carey
authors.affiliation: Department of Neurology, Mayo Clinic College of Medicine, Rochester, Minnesota, United States of America.
authors.forename: Moses
authors.initials: M
authors.lastname: Rodriguez
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D004195:Disease Models, Animal; D000090322:Homeobox Protein Nkx-2.2; D018398:Homeodomain Proteins; D006801:Humans; D020925:Hypoxia-Ischemia, Brain / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D009046:Motor Neurons / Q000378:metabolism* / Q000473:pathology; D009186:Myelin Sheath / Q000378:metabolism / Q000473:pathology; D009419:Nerve Tissue Proteins / Q000096:biosynthesis; D058953:Neural Stem Cells / Q000378:metabolism* / Q000473:pathology; D009687:Nuclear Proteins; D009836:Oligodendroglia / Q000378:metabolism / Q000473:pathology; D014157:Transcription Factors; D066127:White Matter / Q000378:metabolism* / Q000473:pathology
chemical_list: D000090322:Homeobox Protein Nkx-2.2; D018398:Homeodomain Proteins; C000715631:NKX2-2 protein, human; D009419:Nerve Tissue Proteins; C000715627:Nkx2-2 protein, mouse; D009687:Nuclear Proteins; D014157:Transcription Factors