This study investigated the effects of progesterone(P4) on the production and survival of neurons in the hippocampal dentate gyrus of adult male mice.The administration of P4(4 mg/kg) for 3 consecutive days beginning on the 0-2 nd day after the first BrdU-injection(BrdU-D0-2) produced an approximately twofold increase in the number of 28-and 56-day-old BrdU(+) cells in comparison to the controls,whereas it did not alter the number of 24 /48-h-old BrdU(+) cells.P4 preferentially promoted the survival of newborn neurons when administered at BrdU-D5-7,but not at BrdU-D10-12 and BrdU-D15-17.Androstenedione(Ad),testosterone(TE),or estradiol(E2) at the same-dose of P4,when administered at BrdU-D0-2,could not replicate the effect of P4,while the inhibition of 5 alpha-reductase by finasteride did not affect the P4-action,indicating that the P4-effect is exerted by P4 itself but not by its metabolites.On the other hand,the P4R antagonist RU486 partially suppressed the P4-effect,while inhibitors for Src,MEK,or PI3K totally suppressed the P4-effect.Finally,the P4-enhanced survival of newborn neurons was accompanied by a potentiation of spatial learning and memory,which was P4R-dependent.These findings suggest that P4 enhances the survival of newborn neurons through P4R and /or the Src-ERK and PI3K pathways independent of its influence on cell proliferation,which is well correlated with the potentiated spatial cognitive function of P4-treated animals. This study investigated the effects of progesterone (P4) on the production and survival of neurons in the hippocampal dentate gyrus of adult male mice. The administration of P4 (4 mg / kg) for 3 consecutive days beginning on the 0-2 nd day after the first BrdU-injection (BrdU-D0-2) produced an approximately twofold increase in the number of 28-and 56-day-old BrdU (+) cells in comparison to the controls, 48-h-old BrdU (+) cells. P4 preferentially promoted the survival of newborn neurons when administered at BrdU-D5-7, but not at BrdU-D10-12 and BrdU-D15-17. Androstenedione (Ad), testosterone TE), or estradiol (E2) at the same-dose of P4, when administered at BrdU-D0-2, could not replicate the effect of P4, while the inhibition of 5 alpha-reductase by finasteride did not affect the P4-action , indicating that the P4-effect is exerted by P4 itself but not by its metabolites. On the other hand, the P4R antagonist RU486 partially suppressed the P4-effect, while inhibitors for Src, MEK, or PI3K totally suppressed the P4-effect. Finally, the P4-enhanced survival of newborn neurons was accompanied by a potentiation of spatial learning and memory, which was P4R-dependent. These findings suggest that P4 enhances the survival of newborn neurons through P4R and / or the Src-ERK and PI3K pathways independent of its influence on cell proliferation, which is well correlated with the potentiated spatial cognitive function of P4-treated animals.