title: Mild intermittent hypoxemia in neonatal mice causes permanent neurofunctional deficit and white matter hypomyelination.
abstract: Very low birth weight (VLBW) premature infants experience numerous, often self-limited non-bradycardic episodes of intermittent hypoxemia (IH). We hypothesized that these episodes of IH affect postnatal white matter (WM) development causing hypomyelination and neurological handicap in the absence of cellular degeneration. Based on clinical data from ten VLBW neonates; a severity, daily duration and frequency of non-bradycardic IH episodes were reproduced in neonatal mice. Changes in heart rate and cerebral blood flow during IH were recorded. A short-term and long-term neurofunctional performance, cerebral content of myelin basic protein (MBP), 2'3' cyclic-nucleotide 3-phosphodiesterase (CNPase), electron microscopy of axonal myelination and the extent of cellular degeneration were examined. Neonatal mice exposed to IH exhibited no signs of cellular degeneration, yet demonstrated significantly poorer olfactory discrimination, wire holding, beam and bridge crossing, and walking-initiation tests performance compared to controls. In adulthood, IH-mice demonstrated no alteration in navigational memory. However, sensorimotor performance on rota-rod, wire-holding and beam tests was significantly worse compared to naive littermates. Both short- and long-term neurofunctional deficits were coupled with decreased MBP, CNPase content and poorer axonal myelination compared to controls. In neonatal mice mild, non-ischemic IH stress, mimicking that in VLBW preterm infants, replicates a key phenotype of non-cystic WM injury: permanent hypomyelination and sensorimotor deficits. Because this phenotype has developed in the absence of cellular degeneration, our data suggest that cellular mechanisms of WM injury induced by mild IH differ from that of cystic periventricular leukomalacia where the loss of myelin-producing cells and axons is the major mechanism of injury.
authors.affiliation: Department of Pediatrics, Division of Neonatology, Columbia University, New York, USA.
authors.forename: Courtney
authors.initials: C
authors.lastname: Juliano
authors.affiliation: Department of Pediatrics, Division of Neonatology, Columbia University, New York, USA.
authors.forename: Sergey
authors.initials: S
authors.lastname: Sosunov
authors.affiliation: Department of Pediatrics, Division of Neonatology, Columbia University, New York, USA.
authors.forename: Zoya
authors.initials: Z
authors.lastname: Niatsetskaya
authors.affiliation: Department of Pediatrics, Division of Neonatology, Columbia University, New York, USA.
authors.forename: Joseph A
authors.initials: JA
authors.lastname: Isler
authors.affiliation: Department of Pediatrics, Division of Neonatology, Columbia University, New York, USA.
authors.forename: Irina
authors.initials: I
authors.lastname: Utkina-Sosunova
authors.affiliation: Department of Pediatrics, Division of Neonatology, Columbia University, New York, USA.
authors.forename: Isaac
authors.initials: I
authors.lastname: Jang
authors.affiliation: Department of Pediatrics, Division of Neonatology, Columbia University, New York, USA.
authors.forename: Veniamin
authors.initials: V
authors.lastname: Ratner
authors.affiliation: Department of Pediatrics, Division of Neonatology, Columbia University, New York, USA. Electronic address: vt82@cumc.columbia.edu.
authors.forename: Vadim
authors.initials: V
authors.lastname: Ten
mesh_terms: D015087:2',3'-Cyclic-Nucleotide Phosphodiesterases / Q000378:metabolism; D000818:Animals; D000831:Animals, Newborn; D053148:Caspase 3 / Q000378:metabolism; D002560:Cerebrovascular Circulation / Q000502:physiology; D004195:Disease Models, Animal; D018507:Gene Expression Regulation, Developmental / Q000502:physiology*; D006339:Heart Rate / Q000502:physiology; D000860:Hypoxia / Q000150:complications* / Q000628:therapy; D056784:Leukoencephalopathies / Q000209:etiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D053580:Muscle Strength / Q000502:physiology; D004676:Myelin Basic Protein / Q000378:metabolism; D009413:Nerve Fibers, Myelinated / Q000378:metabolism / Q000473:pathology / Q000648:ultrastructure; D009422:Nervous System Diseases / Q000209:etiology*; D010100:Oxygen / Q000008:administration & dosage; D011597:Psychomotor Performance / Q000502:physiology; D018709:Statistics, Nonparametric; D013997:Time Factors
chemical_list: D004676:Myelin Basic Protein; D015087:2',3'-Cyclic-Nucleotide Phosphodiesterases; D053148:Caspase 3; D010100:Oxygen
keywords: Hypomyelination; Intermittent hypoxemia; Model; Sensori-motor deficit; White matter injury