Mild, non-lesioning transient hypoxia in the newborn rat induces delayed brain neurogenesis associated with improved memory scores.

Although neonatal hypoxia can lead to brain damage, mild hypoxic episodes may be beneficial, as illustrated by tolerance induction by preconditioning, a process that might involve neurogenesis. To examine if brief hypoxia in newborn rats could stimulate the generation of neurons, pups were exposed for 5 min to 100% N2. Cell density and apoptosis were monitored in various brain regions and cell proliferation was studied by the incorporation of bromodeoxyuridine. Hypoxia did not result in detectable cell death but promoted cell proliferation in the ensuing three weeks in the subventricular zone and hippocampal dentate gyrus, with increased cell density in hippocampus CA1 pyramidal cells and granular layer of the dentate gyrus. Newly generated cells expressed neuronal markers (NeuroD or neuronal nuclear antigen) and were able to migrate from germinative zones to specific sites, in particular from the subventricular zone to the CA1 layer along the posterior periventricle. Neurogenesis was associated with an early activation of the extracellular regulated kinase 1/2 pathway, and pre-hypoxic administration of U0126, an inhibitor of mitogen-activated protein kinase kinase, impaired hypoxia effect on cell proliferation. Neurobehavioral capacities of hypoxic rats paralleled those of controls, but early exposure to hypoxia was associated with significantly improved memory retrieval scores at 40 days. In conclusion, brief neonatal hypoxia may trigger delayed generation of potentially functional neurons without concomitant cell death. This may constitute an interesting model for studying cell key events involved in the induction of neurogenesis.