There is growing evidence demonstrating that hippocampus-dependent learning can rescue the newly generated neurons from apoptotic cell death, but the underlying mechanism is largely unknown.Here we explored the role of ERK signaling pathway in survival-promoting effect of hippocampus-dependent learning.Mice were injected intraperitoneally with bromodeoxyuridine (BrdU) to label dividing cells.One week later, the mice were trained in Morris water maze for five consecutive days.SL327 (30 mg/kg), an inhibitor of the upstream MAPK/ERK kinase (MEK) and MK801 (0.14 mg/kg), an antagonist of NMDA receptor were injected 30 min respectively before training.Level of extracellular signal-regulated kinase (ERK) phosphorylation was characterized using Western blot.Number of BrdU-labeled cells in dentate gyrus was then counted.Results showed that spatial learning enhanced the survival of immature neurons generated before learning.SL327 did not produce significant impairment in escape latency of spatial learning, although SL327 down-regulated levels of hippocampal ERK phosphorylation.However, SL327 blocked the survival-promoting effect of learning.In contrast, MK801 increased the phosphorylation levels of ERK in hippocampus of the mice.Additionally, MK801 also disrupted the performance of mice on spatial learning and decreased swimming speed of the mice.However, MK801 did not modulate survival-promoting effect of learning.Taken together, our results demonstrate that learning tasks enhance survival of new neurons through ERK-dependent signaling mechanisms but not mediated by activation of NMDA receptor in hippocampus.The current study might provide a possible regulatory strategy of compensating neurogenesis losses associated with neurodegeneration disease and nonpathological ageing.