Abstract
BackgroundMechanisms that affect recovery from fetal and neonatal hypoxic-ischemic (H-I) brain injury have not been fully elucidated. The incidence of intrapartum asphyxia is approximately 2.5%, but the occurrence of adverse clinical outcome is much lower. One of the factors which may account for this relatively good outcome is the process of neurogenesis, which has been described in adult animals. We used a neonatal mouse model to assess new cells in the hippocampus after H-I injury.ResultsNeonatal mice underwent permanent unilateral carotid ligation on the seventh postnatal day followed by exposure to 8% hypoxia for 75 minutes. The presence of new cells was determined by bromodeoxyuridine (BrdU) incorporation into cells with sacrifice of the animals at intervals. Brain sections were stained for BrdU in combination with neuronal, glial, endothelial and microglial stains.We found a significant increase in BrdU-positive cells in the neonatal mouse hippocampus in the injured area compared to the non-injured area, most prominent in the dentate gyrus (DG) (154.5 ± 59.6 v. 92.9 ± 32.7 at 3 days after injury; 68.9 ± 23.4 v. 52.4 ± 17.1 at 35 days after injury, p < 0.0011). Among the cells which showed differentiation, those which were stained as either microglial or endothelial cells showed a peak increase at three days after the injury in the DG, injured versus non-injured side (30.5 ± 17.8 v. 2.7 ± 2.6, p < 0.0002). As in the adult animal, neurogenesis was significantly increased in the DG with injury (15.0 ± 4.6 v. 5.2 ± 1.6 at 35 days after injury, p < 0.0002), and this increase was subsequent to the appearance of the other dividing cells. Numbers of new oligodendrocytes were significantly higher in the DG on the non-injured side (7.0 ± 24.2 v. 0.1 ± 0.3, p < 0.0002), suggesting that oligodendrocyte synthesis was reduced in the injured hippocampus.ConclusionThese findings demonstrate that the neonatal animal responds to brain injury with neurogenesis, much like the adult animal. In addition, H-I insult leads to more neurogenesis than hypoxia alone. This process may play a role in the recovery of the neonatal animal from H-I insult, and if so, enhancement of the process may improve recovery.
Highlights
Mechanisms that affect recovery from fetal and neonatal hypoxic-ischemic (H-I) brain injury have not been fully elucidated
As this process may be relevant to the recovery of the neonatal brain from H-I injury, we sought to determine whether new cells arose in the neonatal brain following this type of injury
Neuronal and other cell regeneration was significantly increased in the dentate gyrus (DG) on the side of the brain exposed to HI injury, as opposed to hypoxic injury alone
Summary
Mechanisms that affect recovery from fetal and neonatal hypoxic-ischemic (H-I) brain injury have not been fully elucidated. Hippocampal stem cells from the adult brain have been demonstrated to proliferate and differentiate into neurons, astrocytes, and oligodendrocytes [3], as a response to multiple factors, including hypoxic-ischemic (H-I) injury, or trauma [4,5]. New neuronal growth has been demonstrated in several studies of adult H-I models, including in humans [6,7,8,9,10], but this finding has received less attention in neonatal animals. The pluripotent stem cells found in the neonatal brain have not been characterized as completely as those in the adult brain As this process may be relevant to the recovery of the neonatal brain from H-I injury, we sought to determine whether new cells arose in the neonatal brain following this type of injury. We employed a neonatal mouse H-I brain injury model with BrdU injection to determine what types of BrdU-positive cells are present in the hippocampus after an H-I event and to determine if this response if different than that due to hypoxia alone
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