Injury and Recovery in Developing Brain

Summary

Principal Investigator: Flora M Vaccarino
Abstract: As many as 50% of low-birth-weight infants suffer cognitive deficits due to chronic hypoxia and circulatory complications. Longitudinal studies suggest recovery in both brain volume and cognitive functions by early adulthood in some children, however this recovery is variable and the neurobiological basis of this improvement are not understood. Our mouse model of chronic sublethal hypoxic injury reproduces the initial cortical volume deficit and ventriculomegaly, as well as the subsequent recovery, although some neuron loss and cognitive abnormalities persist long-term in these mice. Identifying tlie cellular and molecular events that underlie neuronal recovery and finding ways to enhance this process are the common goals of this program project. We hypothesize that recovery from hypoxic brain injury is due to a coupled neurogenic/angiogenic response. This includes (1) proliferation of neural stem cells and progenitors, which requires specific growth factors in neural stem cells and vascular endothelium;(2) survival of newly-born neuronal and glial populations, which requires improved energetic metabolism in the newly-generated cells and trophic influences from neural and vascular compartments. Specific projects in this program will test these hypotheses by generating tissue-specific and time-dependent loss- or gain-of function genetic models to test the function of several proliferative, survival and differentiation factors in neural stem cells, oligodendrocyte progenitors, and vascular endothelium. The factors under investigation include Fibroblast growth factor 2 (FGF2), the Epidermal growth factor receptor (EGFR), TrkB and its ligand Brain derived neurotropic growth factor (BDNF), the mitochondrial uncoupling protein 2 (UCP2) and the gut hormone ghrelin. Elucidating the role of these genes in specific cell types will reveal the reciprocal and dynamic interactions between vascular, neural and metabolic components as the animals recover from injury in standard or enriched environment. A multidisciplinary approach, which includes morphometric and immunocytochemical analyses, electron microscopy and electrophysiology, is used to assess whether the signaling systems under study contribute adaptive changes triggered by the enriched environment in hypoxic animals. Furthermore, the beneficial effect of enhancing specific components of these signaling systems will be tested at the cellular and behaviorallevel. The long-term goal of these studies is to identify new means of therapeutic intervention to decrease the developmental disability and neurobehavioral sequelae of preterm birth.
Funding Period: 2009-09-15 - 2014-06-30
more information: NIH RePORT

Top Publications

  1. pmc Fgfr1 is required for cortical regeneration and repair after perinatal hypoxia
    Devon M Fagel
    Child Study Center, Yale University, New Haven, Connecticut 06520, USA
    J Neurosci 29:1202-11. 2009
  2. pmc Effects of preoperative hypoxia on white matter injury associated with cardiopulmonary bypass in a rodent hypoxic and brain slice model
    Kota Agematsu
    1 Department of Cardiac Surgery, Children s National Medical Center, Washington, DC 2 Center for Neuroscience Research, Children s National Medical Center, Washington, DC
    Pediatr Res 75:618-25. 2014
  3. pmc Intranasal epidermal growth factor treatment rescues neonatal brain injury
    Joseph Scafidi
    1 Center for Neuroscience Research, Children s National Medical Center, Washington DC 20010, USA 2 Department of Neurology, Children s National Medical Center, Washington DC 20010, USA
    Nature 506:230-4. 2014
  4. pmc The mouse aortocaval fistula recapitulates human arteriovenous fistula maturation
    Kota Yamamoto
    Veterans Affairs Connecticut Healthcare Systems, West Haven, Connecticut
    Am J Physiol Heart Circ Physiol 305:H1718-25. 2013
  5. pmc Mitochondrial dynamics controlled by mitofusins regulate Agrp neuronal activity and diet-induced obesity
    Marcelo O Dietrich
    Program in Integrative Cell Signaling and Neurobiology of Metabolism, Section of Comparative Medicine, Yale University School of Medicine, New Haven, CT 06520, USA Department of Biochemistry, Universidade Federal do Rio Grande do Sul, Porto Alegre, RS 90035, Brazil Electronic address
    Cell 155:188-99. 2013
  6. pmc Mitofusin 2 in POMC neurons connects ER stress with leptin resistance and energy imbalance
    Marc Schneeberger
    Diabetes and Obesity Research Laboratory, Institut d Investigacions Biomediques August Pi i Sunyer IDIBAPS, 08036 Barcelona, Spain Department of Endocrinology and Nutrition, Hospital Clínic School of Medicine, University of Barcelona, 08036 Barcelona, Spain Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas Asociadas CIBERDEM, 08036 Barcelona, Spain
    Cell 155:172-87. 2013
  7. pmc Hypoxia-induced developmental delays of inhibitory interneurons are reversed by environmental enrichment in the postnatal mouse forebrain
    Mila Komitova
    Child Study Center, Yale University School of Medicine, New Haven, Connecticut 06520, USA
    J Neurosci 33:13375-87. 2013
  8. pmc Neonatal hyperoxia exposure disrupts axon-oligodendrocyte integrity in the subcortical white matter
    Jonathan Ritter
    Center for Neuroscience Research, Children s National Medical Center, Washington, District of Columbia 20010, USA
    J Neurosci 33:8990-9002. 2013
  9. pmc Rodent brain slice model for the study of white matter injury
    Akira Murata
    Children s National Heart Institute, Children s National Medical Center, Washington, DC Center for Neuroscience Research, Children s National Medical Center, Washington, DC
    J Thorac Cardiovasc Surg 146:1526-1533.e1. 2013
  10. pmc Oligodendrocyte regeneration after neonatal hypoxia requires FoxO1-mediated p27Kip1 expression
    Beata Jablonska
    Children s National Medical Center, Washington, DC 20010 2970, USA
    J Neurosci 32:14775-93. 2012

Research Grants

Detail Information

Publications19

  1. pmc Fgfr1 is required for cortical regeneration and repair after perinatal hypoxia
    Devon M Fagel
    Child Study Center, Yale University, New Haven, Connecticut 06520, USA
    J Neurosci 29:1202-11. 2009
    ..In contrast, there is incomplete recovery of inhibitory neurons after injury, which may account for persistent behavioral deficits...
  2. pmc Effects of preoperative hypoxia on white matter injury associated with cardiopulmonary bypass in a rodent hypoxic and brain slice model
    Kota Agematsu
    1 Department of Cardiac Surgery, Children s National Medical Center, Washington, DC 2 Center for Neuroscience Research, Children s National Medical Center, Washington, DC
    Pediatr Res 75:618-25. 2014
    ..The mechanism remains unknown. We investigated effects of preoperative hypoxia on deep hypothermic circulatory arrest-induced WM injury using a combined experimental paradigm in rodents...
  3. pmc Intranasal epidermal growth factor treatment rescues neonatal brain injury
    Joseph Scafidi
    1 Center for Neuroscience Research, Children s National Medical Center, Washington DC 20010, USA 2 Department of Neurology, Children s National Medical Center, Washington DC 20010, USA
    Nature 506:230-4. 2014
    ....
  4. pmc The mouse aortocaval fistula recapitulates human arteriovenous fistula maturation
    Kota Yamamoto
    Veterans Affairs Connecticut Healthcare Systems, West Haven, Connecticut
    Am J Physiol Heart Circ Physiol 305:H1718-25. 2013
    ..This model is the first animal model of AVF to show a course that recapitulates aspects of human AVF maturation. ..
  5. pmc Mitochondrial dynamics controlled by mitofusins regulate Agrp neuronal activity and diet-induced obesity
    Marcelo O Dietrich
    Program in Integrative Cell Signaling and Neurobiology of Metabolism, Section of Comparative Medicine, Yale University School of Medicine, New Haven, CT 06520, USA Department of Biochemistry, Universidade Federal do Rio Grande do Sul, Porto Alegre, RS 90035, Brazil Electronic address
    Cell 155:188-99. 2013
    ..Overall, our data unmask an important role for mitochondrial dynamics governed by Mfn1 and Mfn2 in Agrp neurons in central regulation of whole-body energy metabolism. ..
  6. pmc Mitofusin 2 in POMC neurons connects ER stress with leptin resistance and energy imbalance
    Marc Schneeberger
    Diabetes and Obesity Research Laboratory, Institut d Investigacions Biomediques August Pi i Sunyer IDIBAPS, 08036 Barcelona, Spain Department of Endocrinology and Nutrition, Hospital Clínic School of Medicine, University of Barcelona, 08036 Barcelona, Spain Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas Asociadas CIBERDEM, 08036 Barcelona, Spain
    Cell 155:172-87. 2013
    ..This previously unrecognized role for MFN2 argues for a crucial involvement in mediating ER stress-induced leptin resistance. ..
  7. pmc Hypoxia-induced developmental delays of inhibitory interneurons are reversed by environmental enrichment in the postnatal mouse forebrain
    Mila Komitova
    Child Study Center, Yale University School of Medicine, New Haven, Connecticut 06520, USA
    J Neurosci 33:13375-87. 2013
    ....
  8. pmc Neonatal hyperoxia exposure disrupts axon-oligodendrocyte integrity in the subcortical white matter
    Jonathan Ritter
    Center for Neuroscience Research, Children s National Medical Center, Washington, District of Columbia 20010, USA
    J Neurosci 33:8990-9002. 2013
    ..Understanding the pathology of premature PWMI injury will allow for the development of interventional strategies to preserve WM integrity and function...
  9. pmc Rodent brain slice model for the study of white matter injury
    Akira Murata
    Children s National Heart Institute, Children s National Medical Center, Washington, DC Center for Neuroscience Research, Children s National Medical Center, Washington, DC
    J Thorac Cardiovasc Surg 146:1526-1533.e1. 2013
    ..To understand better the mechanisms associated with WM injury, we tested the adequacy of a novel ex vivo brain slice model, with a particular focus on how the maturational stage modulates the injury...
  10. pmc Oligodendrocyte regeneration after neonatal hypoxia requires FoxO1-mediated p27Kip1 expression
    Beata Jablonska
    Children s National Medical Center, Washington, DC 20010 2970, USA
    J Neurosci 32:14775-93. 2012
    ..Thus, FoxO1 and p27(Kip1) may serve as promising target molecules for promoting timely oligodendrogenesis in neonatal DWMI...
  11. pmc Environmental enrichment increases the GFAP+ stem cell pool and reverses hypoxia-induced cognitive deficits in juvenile mice
    Natalina Salmaso
    Child Study Center, Yale University School of Medicine, New Haven, Connecticut 06520, USA
    J Neurosci 32:8930-9. 2012
    ....
  12. pmc Chronic perinatal hypoxia reduces glutamate-aspartate transporter function in astrocytes through the Janus kinase/signal transducer and activator of transcription pathway
    Matthew Raymond
    Center for Neuroscience Research, Children s National Medical Center, Washington, DC 20010, USA
    J Neurosci 31:17864-71. 2011
    ....
  13. pmc Environmental enrichment rescues postnatal neurogenesis defect in the male and female Ts65Dn mouse model of Down syndrome
    Lina Chakrabarti
    Center for Neuroscience Research, Children s National Medical Center, Washington, DC, USA
    Dev Neurosci 33:428-41. 2011
    ....
  14. pmc Cortical glial fibrillary acidic protein-positive cells generate neurons after perinatal hypoxic injury
    Baoyuan Bi
    Child Study Center, Yale University School of Medicine, New Haven, Connecticut 06520, USA
    J Neurosci 31:9205-21. 2011
    ..Our data support the conclusion that hypoxia promotes pluripotency in GFAP(+) cells in the cortical parenchyma. Such plasticity possibly explains the cognitive recovery found in some preterm children...
  15. ncbi GSK-3β: a signaling pathway node modulating neural stem cell and endothelial cell interactions
    Qi Li
    Department of Pathology, School of Medicine, Yale University, 310 Cedar Street, P O Box 208023, New Haven, CT 06520 8023, USA
    Angiogenesis 14:173-85. 2011
    ..Lastly, the therapeutic potential of targeting GSK-3β is discussed...
  16. pmc Modeling premature brain injury and recovery
    Joey Scafidi
    Center for Neuroscience Research, Children s National Medical Center, Washington, DC 20010, USA
    Int J Dev Neurosci 27:863-71. 2009
    ....
  17. pmc Precursors with glial fibrillary acidic protein promoter activity transiently generate GABA interneurons in the postnatal cerebellum
    John Silbereis
    Child Study Center, Yale University School of Medicine, New Haven, CT 06520, USA
    Stem Cells 27:1152-63. 2009
    ..This restricted critical period implies that powerful inhibitory factors may restrict their fate potential in vivo at later stages of development...
  18. pmc Hypoxic injury during neonatal development in murine brain: correlation between in vivo DTI findings and behavioral assessment
    Halima Chahboune
    Department of Diagnostic Radiology, Yale University, New Haven, CT 06510, USA
    Cereb Cortex 19:2891-901. 2009
    ..Thus, CSH mice revealed developmental and behavioral deficits that are similar to those observed in low birth weight preterm infants...
  19. pmc Neurogenesis and maturation in neonatal brain injury
    Natalina Salmaso
    Child Study Center, Yale University, 230 South Frontage Road, New Haven, CT 06520, USA
    Clin Perinatol 41:229-39. 2014
    ....

Research Grants30

  1. Tissue injury and inflammation in MS (P50)
    Bruce D Trapp; Fiscal Year: 2013
    ..abstract_text> ..
  2. Molecular Mechanisms linking Aging, Abeta Proteotoxicity and Neurodegeneration
    Jeffery W Kelly; Fiscal Year: 2013
    ..abstract_text> ..