Oxygen deprivation is a major cause of neurodevelopmental impairments in preterm infants. Cortical gray matter loss and cognitive disability improve over time in some children, while others remain cognitively impaired. The mechanisms underlying this variable recovery are unknown. Our mouse model of chronic sublethal hypoxia reproduces the initial brain atrophy as well as the subsequent recovery in brain structure. In the recovery period following hypoxia, we observed increased proliferation of neural stem and progenitor cells (NSC/NPCs) as well as generation of new cortical neurons from these precursors. Despite this, long-term deficits in working memory persist in the hypoxia-reared animals and significant decreases in the number of GABA interneurons remain in the cerebral cortex. The goals of Project 1 are to investigate the mechanisms for the differential response of excitatory and inhibitory neurons to hypoxia and enhance anatomical and functional recovery following the insult.
In Aim 1, we will study whether the long-term interneuron deficiency after hypoxia is due to a loss of cells or to a deficient maturation of GABAergic inhibitory properties by immunocytochemical and electrophysiological analyses in Gad1[GFP/+] mice.
In Aim 2, we will examine whether environmental enrichment promotes the generation of new excitatory and inhibitory neurons and glial cells from GFAP+ NSC/NPCs or their survival and synaptic integration into the circuitry. These studies will use genetic fate mapping in GFAP-CreERT2 mice and, in collaboration with Projects 3 and 4, electrophysiology and electron microscopy.
In Aim 3 we will examine whether BDNF signaling is required for the beneficial effects of environmental enrichment on neuronal survival by comparing wild type and TrkB-null cell lineages in mice with inducible deletion of TrkB receptors in GFAP+ cells.
In Aim 4 we will test whether exogenously increased FGF signaling, together with environmental enrichment, improves motor and cognitive function by enhancing inhibitory interneuron development after hypoxic insult, including the maturation of their synaptic connections probed by ultrastructural studies. Identifying the crucial cell populations and molecular ingredients that are required for appropriate reconstitufion of neurons and glial cells in cortex will permit us to enhance these growth-promoting responses in critically ill children.

Public Health Relevance

The goal of Project 1 is to understand whether chronic sublethal hypoxia impairs the survival or the maturation of inhibitory neurons in the developing cerebral cortex and whether this can be overcome by enhancing neurogenesis and neuronal survival from endogenous neural stem cells. Understanding the specific neurotrophic factors that mediate neurogenesis and survival after injury will allow to develop new means of therapeutic intervention to decrease the neurobehavioral sequelae of preterm birth.

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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