Hypoxic ischemic (HI) insult damages premature white matter and grey matter in infants and causes significant mortality and morbidity. To investigate the pathological mechanisms of neonatal HI injury and find satisfactory treatments, animal models of neonatal hypoxic ischemic injury have been established and widely used. In this project, novel in vivo magnetic resonance imaging and computational techniques will be used to examine the spatiotemporal evolution of HI injury in a neonatal mouse model. Longitudinal multi-contrast MRI data will be collected and analyzed with co-registered end-point histological data in a common framework based on our MR based atlas of the developing mouse brain.
In aim 1, we will examine grey and white matter injury using in vivo MRI/histology combined analysis.
In aim 2, we will examine neurodegeneration in the cortex, hippocampus, and cerebellum using oscillating gradient diffusion MRI and histology.
In aim3, we will integrate the longitudinal multi-contrast MRI data with histological data in the central framework to characterize the spatiotemporal progression of neonatal HI injury and its regional specificity. We will then use the tools developed here to characterize HI injury in mice lacking functional Fas death receptor. We will also examine the neuroprotective effects of necrostatin in this model. We expect the project to provide detailed maps of temporal course of injury and regional susceptibility, extend our knowledge on the relationships between pathology and diagnostic markers in the mouse model, and shed light on the mechanisms of HI injury and potential treatments. This information and techniques developed in this project will be useful to design effective strategies for intervention and to monitor treatment response in studies using this or similar models.

Public Health Relevance

Neonatal hypoxic ischemic (HI) injury causes significant mortality and morbidity. To find satisfactory treatment, we will examine the complex spatiotemporal patterns of neonatal HI injury in a well-established mouse model using in vivo longitudinal multi-contrast magnetic resonance imaging data and histology.

National Institute of Health (NIH)
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Research Project (R01)
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Developmental Brain Disorders Study Section (DBD)
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Krotoski, Danuta
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Johns Hopkins University
Schools of Medicine
United States
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Wu, Dan; Reisinger, Dominik; Xu, Jiadi et al. (2014) Localized diffusion magnetic resonance micro-imaging of the live mouse brain. Neuroimage 91:12-20
Aggarwal, Manisha; Burnsed, Jennifer; Martin, Lee J et al. (2014) Imaging neurodegeneration in the mouse hippocampus after neonatal hypoxia-ischemia using oscillating gradient diffusion MRI. Magn Reson Med 72:829-40
Wu, Dan; Martin, Lee J; Northington, Frances J et al. (2014) Oscillating gradient diffusion MRI reveals unique microstructural information in normal and hypoxia-ischemia injured mouse brains. Magn Reson Med 72:1366-74