Astroglial cells proliferate in the subventricular zone (SVZ) in the recovery period after perinatal hypoxic injury. While we know a great deal about the astroglial precursor cells/stem cells in the normal developing brain, and how these cells generate neurons for the olfactory bulb, we are still far from understanding whether and how these astroglial precursors contribute to brain repair after injury. This proposal addresses this clinically relevant issue by asking whether reactive astroglial cells give rise to new cortical neurons and oligodendrocytes in the cerebral cortex after chronic perinatal hypoxia, what types of neurons arise from these cells in the normal and injured cerebral cortex, and whether these neurons are electrophysiologically active and normally integrated in the cortical circuitry. This will be accomplished by genetically marking astroglial cells with reporter genes using a transgenic mouse carrying a drug-inducible Cre recombinase gene expressed under the GFAP promoter. Second, we will investigate whether the astroglial precursor cells that give rise to cortical neurons are located in the SVZ and subsequently migrate to the cerebral cortex or whether they are homed within the cortex. For this, we will activate reporter gene expression in local populations of Gfap+ cells via microinjection of a viral vector, or, in a different approach, we will FACS-purify marked Gfap+ cells from cortex or SVZ and follow their fate after transplantation. Third, we will ascertain the gene expression profile that characterizes Gfap+ cells of the SVZ after hypoxia, as opposed to Gfap+ cells present in the cortical parenchyma. The resulting candidate genes will be overexpressed in mouse pups to assess whether they are sufficient to induce cortical neurogenesis. One of these candidate genes is the Fibroblast Growth Factor Receptor 1 (Fgfr1), which is greatly upregulated after perinatal hypoxia. To test whether Fgfr1 is required for the regeneration of cortical neurons that we have observed in hypoxically reared mice, this gene will be deleted in postnatal Gfap+ cells using our inducible Cre transgenic mice. Our results should suggest novel approaches involving exogenous or endogenous astroglial precursors to improve recovery in pediatric patients suffering from hypoxic encephalopathy. Hypoxia?low oxygen?is a relatively frequent cause of brain injury in premature birth or other birth-related complications. Hypoxia often results in devastating consequences, from spasticity to mental disability, for which there is no available therapy. Emerging clinical data suggest that a portion of the prematurely-born children undergo remarkable cognitive improvements over the years. This is mirrored by our observations that mice can regenerate cortical neurons following a perinatal hypoxic insult. We believe that this recovery is due to neural stem cells naturally present in the brain, which react to hypoxia and regenerate the neurons and glia that are lost. Our proposal focuses on the cells that are involved in this regenerative process. By targeting these cells with a genetic marker we will follow their fate and investigate the molecular factors that allow this remarkable cellular replacement to occur. Thus, using our clinically-relevant mouse model, this proposal will permit us to enhance these growth-promoting responses and it will define the crucial cell population and molecular ingredients that are required for appropriate reconstitution of neurons and glial cells in cortex. Importantly, the regenerative processes investigated in this proposal could be mimicked in adult and aged individuals, in which unfortunately cortical neuron loss is not recovered.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Research Project (R01)
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Special Emphasis Panel (ZRG1-BDCN-N (02))
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Owens, David F
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Yale University
Schools of Medicine
New Haven
United States
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Salmaso, Natalina; Jablonska, Beata; Scafidi, Joseph et al. (2014) Neurobiology of premature brain injury. Nat Neurosci 17:341-6
Salmaso, Natalina; Tomasi, Simone; Vaccarino, Flora M (2014) Neurogenesis and maturation in neonatal brain injury. Clin Perinatol 41:229-39
Komitova, Mila; Xenos, Dionysios; Salmaso, Natalina et al. (2013) Hypoxia-induced developmental delays of inhibitory interneurons are reversed by environmental enrichment in the postnatal mouse forebrain. J Neurosci 33:13375-87
Salmaso, Natalina; Silbereis, John; Komitova, Mila et al. (2012) Environmental enrichment increases the GFAP+ stem cell pool and reverses hypoxia-induced cognitive deficits in juvenile mice. J Neurosci 32:8930-9
Bi, Baoyuan; Salmaso, Natalina; Komitova, Mila et al. (2011) Cortical glial fibrillary acidic protein-positive cells generate neurons after perinatal hypoxic injury. J Neurosci 31:9205-21
Silbereis, John; Heintz, Tristan; Taylor, Mary Morgan et al. (2010) Astroglial cells in the external granular layer are precursors of cerebellar granule neurons in neonates. Mol Cell Neurosci 44:362-73
Komitova, Mila; Vaccarino, Flora M (2010) Exciting news from the adult mouse subventricular zone. Front Neurosci 4:23
Chahboune, Halima; Ment, Laura R; Stewart, William B et al. (2009) Hypoxic injury during neonatal development in murine brain: correlation between in vivo DTI findings and behavioral assessment. Cereb Cortex 19:2891-901
Silbereis, John; Cheng, Elise; Ganat, Yosif M et al. (2009) Precursors with glial fibrillary acidic protein promoter activity transiently generate GABA interneurons in the postnatal cerebellum. Stem Cells 27:1152-63
Fagel, Devon M; Ganat, Yosif; Cheng, Elise et al. (2009) Fgfr1 is required for cortical regeneration and repair after perinatal hypoxia. J Neurosci 29:1202-11

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