Chronic hypoxia in children that survive premature birth leads to brain atrophy, presumably due to death of neurons and glia and altered proliferation and differentiation of their progenitors. However, structural MRI studies also indicate that there is progressive recovery of cortical gray matter volume in these children as well as an overgrowth of gray matter in specific cortical regions. In addition, functional MRI studies also suggest intriguing changes in cortical representation of language. Both results suggest that the developing brain can undergo extensive reorganization in cortical connectivity, possibly adaptive in nature. To investigate the mechanisms and the implications of these events, we used our hypoxic mouse model, which reproduces the initial brain atrophy and the subsequent recovery, and reared these mice in enriched environment. We will use a multidisciplinary approach to investigate whether cortical connections change after an early postnatal hypoxic insult and the contribution of adaptive changes in mitochondrial bioenergetics to these events. We identified and characterized mitochondrial uncoupling protein 2 (UCP2), as a critical mitochondrial protein that enables adaptation and survival of neurons under cellular stress, including that triggered by early postnatal hypoxia. UCP2 promotes mitochondrial biogenesis, suppresses intracellular free radical levels, increases synaptogenesis and promotes survival of cell under hypoxia and ischemia. UCP2 was also found critical for the metabolic adaptation of neurons during environmental enrichment, whereby shifts in mitochondrial bioenergetics favored cellular survival and synaptic plasticity. Our central hypothesis is that improved mitochondrial bioenergetics regulated by UCP2 is a key determinant of adaptive changes in neuronal development and connectivity enhancing recovery after a hypoxic event. In this proposal.
Specific Aim 1 will elucidate the profile of mitochondrial bioenergetics in the brain of pups after early postnatal hypoxic insult.
Specific Aim 2 will determine whether neuronal connections change after early postnatal hypoxia, and how these connections are altered by rearing the mice in enriched environment. The execution of the above specific aims will provide new insights into the pathogenesis of neuronal abnormalities triggered by developmental hypoxia.

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Project 4 will determine the role of mitochondrial bioenergetics and its adaptation to promote recovery after perinatal hypoxia. The result will deliver new approaches to decrease harmful effects of hypoxia on the developing brain.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Research Program Projects (P01)
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National Institute of Neurological Disorders and Stroke Initial Review Group (NSD)
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Yale University
New Haven
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