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 undertying 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, longterm 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 Gadl'^''^^* mice.
In Aim 2, we will examine whether environmental enrichment promotes the generafion of new excitatory and inhibitory neurons and glial cells from GFAP+ NSC/NPCs or their survival and synapfic integrafion 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 delefion 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 funcfion by enhancing inhibitory interneuron development after hypoxic insult, including the maturation of their synaptic connecfions 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)
Project #
Application #
Study Section
National Institute of Neurological Disorders and Stroke Initial Review Group (NSD)
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Yale University
New Haven
United States
Zip Code
Kuwahara, Go; Hashimoto, Takuya; Tsuneki, Masayuki et al. (2017) CD44 Promotes Inflammation and Extracellular Matrix Production During Arteriovenous Fistula Maturation. Arterioscler Thromb Vasc Biol 37:1147-1156
Sadaghianloo, Nirvana; Yamamoto, Kota; Bai, Hualong et al. (2017) Increased Oxidative Stress and Hypoxia Inducible Factor-1 Expression during Arteriovenous Fistula Maturation. Ann Vasc Surg 41:225-234
Jablonska, Beata; Gierdalski, Marcin; Chew, Li-Jin et al. (2016) Sirt1 regulates glial progenitor proliferation and regeneration in white matter after neonatal brain injury. Nat Commun 7:13866
Salmaso, Natalina; Dominguez, Moises; Kravitz, Jacob et al. (2015) Contribution of maternal oxygenic state to the effects of chronic postnatal hypoxia on mouse body and brain development. Neurosci Lett 604:12-7
Koch, Marco; Varela, Luis; Kim, Jae Geun et al. (2015) Hypothalamic POMC neurons promote cannabinoid-induced feeding. Nature 519:45-50
Dimou, L; Gallo, V (2015) NG2-glia and their functions in the central nervous system. Glia 63:1429-51
Zonouzi, Marzieh; Scafidi, Joseph; Li, Peijun et al. (2015) GABAergic regulation of cerebellar NG2 cell development is altered in perinatal white matter injury. Nat Neurosci 18:674-82
Hall, Michael R; Yamamoto, Kota; Protack, Clinton D et al. (2015) Temporal regulation of venous extracellular matrix components during arteriovenous fistula maturation. J Vasc Access 16:93-106
Dietrich, Marcelo O; Zimmer, Marcelo R; Bober, Jeremy et al. (2015) Hypothalamic Agrp neurons drive stereotypic behaviors beyond feeding. Cell 160:1222-32
Agematsu, Kota; Korotcova, Ludmila; Scafidi, Joseph et al. (2014) Effects of preoperative hypoxia on white matter injury associated with cardiopulmonary bypass in a rodent hypoxic and brain slice model. Pediatr Res 75:618-25

Showing the most recent 10 out of 32 publications