The long term objective of these studies is to identify cellular mechanisms of hypoxic-ischemic fetal cerebral white matter injury and provide clinically-relevant insight into the histopathological substrates of lesions defined by MR imaging.
The specific aims are to: 1) employ high-field strength ex vivo MR imaging to determine the distribution of chronic white matter lesions and use cell-specific and cell death markers to determine the relative sensitivity and specificity of contrast and diffusion-weighted MR imaging;2) elucidate specific molecular mechanisms by which chronic demyelination and oligodendrocyte maturation arrest occur in a slice-culture model enriched in vulnerable white matter;and 3) determine if chronic white matter injury results in a persistent state of vulnerability to ischemia, which is needed to establish better clinical care for critically ill preterm infants at risk for multiple episodes of ischemia and hypotension. To achieve these objectives an in utero preparation in the 0.65 gestation sheep will be utilized in which ischemia will be induced in fetuses through the inflation of occluders placed on the bilateral carotid arteries. Acquisition of MRI data, using a Bruker Biospin small animal imaging system that is equipped with an ultra- high field (12 T) magnet, will include T2 and diffusion anisotropy measures to assess the cellular etiology of lesions shown on MRI. Tissue sections will be stained immunofluorescently for major cell types found to be enriched in the lesions in preliminary studies (oligodendrocytes, astrocytes, macrophages, microglia, and degenerating cells) and then co-registered with lesions identified with MR imaging. Organotypic slice culture will be used to study the effect of specific molecular interactions on the developing and injured white matter. Chronic injured white matter represents a potentially clinically important state whereby preterm infants that suffer cerebral injury remain susceptible to injury over an extended developmental window and may even acquire increased susceptibility to recurrent injury. We will determine if recurrent ischemia imparts increased susceptibility or resistance on glia and axons in our ovine model of white matter injury.

Public Health Relevance

Premature birth is a common clinical problem that results in deleterious consequences for motor and cognitive development resulting in cerebral palsy and related learning disabilities by largely unknown pathogenic mechanisms. Upon completion of this project, imaging, cellular and molecular analysis of chronic white lesions will be combined in a translationally-relevant model. We expect to gain fundamental new insights into pathogenetic mechanisms that trigger disturbances in myelination and result in permanent neurological disabilities.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Individual Predoctoral NRSA for M.D./Ph.D. Fellowships (ADAMHA) (F30)
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NST-2 Subcommittee (NST)
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Hicks, Ramona R
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Oregon Health and Science University
Schools of Medicine
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Hagen, Matthew W; Riddle, Art; McClendon, Evelyn et al. (2014) Role of recurrent hypoxia-ischemia in preterm white matter injury severity. PLoS One 9:e112800
Dean, Justin M; McClendon, Evelyn; Hansen, Kelly et al. (2013) Prenatal cerebral ischemia disrupts MRI-defined cortical microstructure through disturbances in neuronal arborization. Sci Transl Med 5:168ra7
Riddle, Art; Maire, Jennifer; Cai, Victor et al. (2013) Hemodynamic and metabolic correlates of perinatal white matter injury severity. PLoS One 8:e82940
Alix, James J P; Zammit, Christian; Riddle, Art et al. (2012) Central axons preparing to myelinate are highly sensitive [corrected] to ischemic injury. Ann Neurol 72:936-51
Back, Stephen A; Riddle, Art; Dean, Justin et al. (2012) The instrumented fetal sheep as a model of cerebral white matter injury in the premature infant. Neurotherapeutics 9:359-70
Brambrink, Ansgar M; Back, Stephen A; Riddle, Art et al. (2012) Isoflurane-induced apoptosis of oligodendrocytes in the neonatal primate brain. Ann Neurol 72:525-35
Uchida, Nobuko; Chen, Kevin; Dohse, Monika et al. (2012) Human neural stem cells induce functional myelination in mice with severe dysmyelination. Sci Transl Med 4:155ra136
Riddle, Art; Maire, Jennifer; Gong, Xi et al. (2012) Differential susceptibility to axonopathy in necrotic and non-necrotic perinatal white matter injury. Stroke 43:178-84
Buser, Joshua R; Maire, Jennifer; Riddle, Art et al. (2012) Arrested preoligodendrocyte maturation contributes to myelination failure in premature infants. Ann Neurol 71:93-109
Riddle, Art; Dean, Justin; Buser, Joshua R et al. (2011) Histopathological correlates of magnetic resonance imaging-defined chronic perinatal white matter injury. Ann Neurol 70:493-507

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