Abbreviated Exposure to Hypoxia Is Sufficient to Induce CNS Dysmyelination, Modulate Spinal Motor Neuron Composition, and Impair Motor Development in Neonatal Mice

Jens O. Watzlawik, Robert J. Kahoud, Ryan J. O'Toole, Katherine A M White, Alyssa R. Ogden, Meghan M. Painter, Bharath Wootla, Louisa M. Papke, Aleksandar Denic, Jill M. Weimer, William A. Carey, Moses Rodriguez

Research output: Contribution to journalArticle

6 Citations (Scopus)

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.

Original languageEnglish (US)
Article numbere0128007
JournalPLoS One
Volume10
Issue number5
DOIs
StatePublished - May 28 2015

Fingerprint

motor development
Motor Neurons
motor neurons
Neurons
hypoxia
neonates
Brain
Wounds and Injuries
Cell death
Chemical analysis
brain
axons
stem cells
cell death
Foster Home Care
neurons
cerebral palsy
Oligodendroglia
Axons
myelin sheath

ASJC Scopus subject areas

  • Agricultural and Biological Sciences(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Medicine(all)

Cite this

Watzlawik, J. O., Kahoud, R. J., O'Toole, R. J., White, K. A. M., Ogden, A. R., Painter, M. M., ... Rodriguez, M. (2015). Abbreviated Exposure to Hypoxia Is Sufficient to Induce CNS Dysmyelination, Modulate Spinal Motor Neuron Composition, and Impair Motor Development in Neonatal Mice. PLoS One, 10(5), [e0128007]. https://doi.org/10.1371/journal.pone.0128007

Abbreviated Exposure to Hypoxia Is Sufficient to Induce CNS Dysmyelination, Modulate Spinal Motor Neuron Composition, and Impair Motor Development in Neonatal Mice. / Watzlawik, Jens O.; Kahoud, Robert J.; O'Toole, Ryan J.; White, Katherine A M; Ogden, Alyssa R.; Painter, Meghan M.; Wootla, Bharath; Papke, Louisa M.; Denic, Aleksandar; Weimer, Jill M.; Carey, William A.; Rodriguez, Moses.

In: PLoS One, Vol. 10, No. 5, e0128007, 28.05.2015.

Research output: Contribution to journalArticle

Watzlawik, JO, Kahoud, RJ, O'Toole, RJ, White, KAM, Ogden, AR, Painter, MM, Wootla, B, Papke, LM, Denic, A, Weimer, JM, Carey, WA & Rodriguez, M 2015, 'Abbreviated Exposure to Hypoxia Is Sufficient to Induce CNS Dysmyelination, Modulate Spinal Motor Neuron Composition, and Impair Motor Development in Neonatal Mice', PLoS One, vol. 10, no. 5, e0128007. https://doi.org/10.1371/journal.pone.0128007
Watzlawik, Jens O. ; Kahoud, Robert J. ; O'Toole, Ryan J. ; White, Katherine A M ; Ogden, Alyssa R. ; Painter, Meghan M. ; Wootla, Bharath ; Papke, Louisa M. ; Denic, Aleksandar ; Weimer, Jill M. ; Carey, William A. ; Rodriguez, Moses. / Abbreviated Exposure to Hypoxia Is Sufficient to Induce CNS Dysmyelination, Modulate Spinal Motor Neuron Composition, and Impair Motor Development in Neonatal Mice. In: PLoS One. 2015 ; Vol. 10, No. 5.
@article{ab470c5f87cd42d79773d67e1d6dff80,
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.",
author = "Watzlawik, {Jens O.} and Kahoud, {Robert J.} and O'Toole, {Ryan J.} and White, {Katherine A M} and Ogden, {Alyssa R.} and Painter, {Meghan M.} and Bharath Wootla and Papke, {Louisa M.} and Aleksandar Denic and Weimer, {Jill M.} and Carey, {William A.} and Moses Rodriguez",
year = "2015",
month = "5",
day = "28",
doi = "10.1371/journal.pone.0128007",
language = "English (US)",
volume = "10",
journal = "PLoS One",
issn = "1932-6203",
publisher = "Public Library of Science",
number = "5",

}

TY - JOUR

T1 - Abbreviated Exposure to Hypoxia Is Sufficient to Induce CNS Dysmyelination, Modulate Spinal Motor Neuron Composition, and Impair Motor Development in Neonatal Mice

AU - Watzlawik, Jens O.

AU - Kahoud, Robert J.

AU - O'Toole, Ryan J.

AU - White, Katherine A M

AU - Ogden, Alyssa R.

AU - Painter, Meghan M.

AU - Wootla, Bharath

AU - Papke, Louisa M.

AU - Denic, Aleksandar

AU - Weimer, Jill M.

AU - Carey, William A.

AU - Rodriguez, Moses

PY - 2015/5/28

Y1 - 2015/5/28

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=84934979526&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84934979526&partnerID=8YFLogxK

U2 - 10.1371/journal.pone.0128007

DO - 10.1371/journal.pone.0128007

M3 - Article

VL - 10

JO - PLoS One

JF - PLoS One

SN - 1932-6203

IS - 5

M1 - e0128007

ER -