Sustained neocortical neurogenesis after neonatal hypoxic/ischemic injury.
OBJECTIVE
Neocortical neurons are sensitive to hypoxic-ischemic (H-I) injuries at term and their demise contributes to neurological disorders. Here we tested the hypothesis that the subventricular zone of the immature brain regenerates neocortical neurons, and that this response is sustained.


METHODS
Systemic injections of 5-bromo-2'-deoxyuridine (BrdU) and intraventricular injections of replication-deficient retroviruses were used to label newly born cells, and confocal microscopy after immunofluorescence was used to phenotype the new cells from several days to several months after perinatal H-I in the postnatal day 6 rat. Quantitative polymerase chain reaction was used to evaluate chemoattractants, growth factors, and receptors.


RESULTS
Robust production of new neocortical neurons after perinatal H-I occurs. These new neurons are descendants of the subventricular zone, and they colonize the cell-sparse columns produced by the injury to the neocortex. These columns are populated by reactive astrocytes and microglia. Surprisingly, this neuronogenesis is sustained for months. Molecular analyses demonstrated increased neocortical production of insulin-like growth factor-1 and monocyte chemoattractant factor-1 (but statistically insignificant production of erythropoietin, brain-derived neurotrophic factor, glial-derived neurotrophic factor, and transforming growth factor-alpha).


CONCLUSIONS
The young nervous system has long been known to possess a greater capacity to recover from injury than the adult system. Our data indicate that H-I injury in the neonatal brain initiates an enduring regenerative response from the subventricular zone. These data suggest that additional mechanisms than those previously surmised contribute to the remarkable ability of the immature brain to recover from injury.
Yang
Zhengang
Z
Department of Neurology and Neurosciences, UMDNJ-New Jersey Medical School, New Jersey Institute of Technology, Newark, NJ 07103, USA.
Covey
Matthew V
MV
Bitel
Claudine L
CL
Ni
Li
L
Jonakait
G Miller
GM
Levison
Steven W
SW
D000818:Animals; D000831:Animals, Newborn; D018925:Chemokines / Q000096:biosynthesis; D005455:Fluorescent Antibody Technique; D020925:Hypoxia-Ischemia, Brain / Q000473:pathology* / Q000503:physiopathology; D018613:Microscopy, Confocal; D019579:Neocortex / Q000166:cytology* / Q000293:injuries / Q000502:physiology; D009416:Nerve Regeneration / Q000502:physiology*; D009474:Neurons / Q000166:cytology* / Q000378:metabolism / Q000473:pathology; D051381:Rats; D019707:Receptors, Chemokine / Q000096:biosynthesis; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013234:Stem Cells / Q000166:cytology* / Q000378:metabolism
D018925:Chemokines; D019707:Receptors, Chemokine