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.

Public Health Relevance

Preterm birth is one of the major pediatric public health problems of our time. The goal of this P01 is to identify the adaptive mechanisms that underlie the anatomical and behavioral recovery that occurs in some of these children. This will permit to enhance these mechanisms in those who cannot recover, identifying new means of therapeutic intervention to decrease the neurobehavioral sequelae of preterm birth. This will be approached under the auspices of four interrelated projects and two cores, all using our mouse model of sublethal hypoxic injury.

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)
Program Officer
Koenig, James I
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Yale University
Schools of Medicine
New Haven
United States
Zip Code
Salmaso, Natalina; Jablonska, Beata; Scafidi, Joseph et al. (2014) Neurobiology of premature brain injury. Nat Neurosci 17:341-6
Kim, Jae Geun; Suyama, Shigetomo; Koch, Marco et al. (2014) Leptin signaling in astrocytes regulates hypothalamic neuronal circuits and feeding. Nat Neurosci 17:908-10
Gallo, Vittorio; Deneen, Benjamin (2014) Glial development: the crossroads of regeneration and repair in the CNS. Neuron 83:283-308
Salmaso, Natalina; Tomasi, Simone; Vaccarino, Flora M (2014) Neurogenesis and maturation in neonatal brain injury. Clin Perinatol 41:229-39
Scafidi, Joseph; Hammond, Timothy R; Scafidi, Susanna et al. (2014) Intranasal epidermal growth factor treatment rescues neonatal brain injury. Nature 506:230-4
Gallo, Vittorio (2014) Lethal migration: the bradykinin story. J Physiol 592:4805-6
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
Dietrich, Marcelo O; Liu, Zhong-Wu; Horvath, Tamas L (2013) Mitochondrial dynamics controlled by mitofusins regulate Agrp neuronal activity and diet-induced obesity. Cell 155:188-99
Murata, Akira; Agematsu, Kota; Korotcova, Ludmila et al. (2013) Rodent brain slice model for the study of white matter injury. J Thorac Cardiovasc Surg 146:1526-1533.e1
Schneeberger, Marc; Dietrich, Marcelo O; Sebastian, David et al. (2013) Mitofusin 2 in POMC neurons connects ER stress with leptin resistance and energy imbalance. Cell 155:172-87

Showing the most recent 10 out of 19 publications