title: Spectrum of short- and long-term brain pathology and long-term behavioral deficits in male repeated hypoxic rats closely resembling human extreme prematurity.
abstract: Brain injury in the premature infant is associated with a high risk of neurodevelopmental disability. Previous small-animal models of brain injury attributable to extreme prematurity typically fail to generate a spectrum of pathology and behavior that closely resembles that observed in humans, although they provide initial answers to numerous cellular, molecular, and therapeutic questions. We tested the hypothesis that exposure of rats to repeated hypoxia from postnatal day 1 (P1) to P3 models the characteristic white matter neuropathological injury, gray matter volume loss, and memory deficits seen in children born extremely prematurely. Male Sprague Dawley rats were exposed to repeated hypoxia or repeated normoxia from P1 to P3. The absolute number of pre-oligodendrocytes and mature oligodendrocytes, the surface area and g-ratio of myelin, the absolute volume of cerebral white and gray matter, and the absolute number of cerebral neurons were quantified stereologically. Spatial memory was investigated on a radial arm maze. Rats exposed to repeated hypoxia had a significant loss of (1) pre-oligodendrocytes at P4, (2) cerebral white matter volume and myelin at P14, (3) cerebral cortical and striatal gray matter volume without neuronal loss at P14, and (4) cerebral myelin and memory deficits in adulthood. Decreased myelin was correlated with increased attention deficit hyperactivity disorder-like hyperactivity. This new small-animal model of extreme prematurity generates a spectrum of short- and long-term pathology and behavior that closely resembles that observed in humans. This new rat model provides a clinically relevant tool to investigate numerous cellular, molecular, and therapeutic questions on brain injury attributable to extreme prematurity.
authors.affiliation: Department of Anatomy, Otago School of Medical Sciences, Department of Psychology, and Brain Health Research Centre, University of Otago, Dunedin 9054, New Zealand. dorothy.oorschot@anatomy.otago.ac.nz
authors.forename: Dorothy E
authors.initials: DE
authors.lastname: Oorschot
authors.forename: Logan
authors.initials: L
authors.lastname: Voss
authors.forename: Matthew V
authors.initials: MV
authors.lastname: Covey
authors.forename: Liping
authors.initials: L
authors.lastname: Goddard
authors.forename: William
authors.initials: W
authors.lastname: Huang
authors.forename: Penny
authors.initials: P
authors.lastname: Birchall
authors.forename: David K
authors.initials: DK
authors.lastname: Bilkey
authors.forename: Sarah E
authors.initials: SE
authors.lastname: Kohe
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D001253:Astrocytes / Q000378:metabolism / Q000473:pathology; D001522:Behavior, Animal / Q000502:physiology*; D001921:Brain / Q000378:metabolism / Q000473:pathology* / Q000503:physiopathology; D000860:Hypoxia / Q000378:metabolism / Q000473:pathology* / Q000503:physiopathology; D008297:Male; D018782:Maze Learning / Q000502:physiology*; D009186:Myelin Sheath / Q000378:metabolism / Q000473:pathology; D009413:Nerve Fibers, Myelinated / Q000473:pathology; D009474:Neurons / Q000378:metabolism / Q000473:pathology*; D009836:Oligodendroglia / Q000473:pathology; D051381:Rats; D017207:Rats, Sprague-Dawley