Decreased neurogenesis in aged rats results from loss of granule cell precursors without lengthening of the cell cycle

It is well established that neurogenesis in the dentate gyrus slows with aging, but it is unclear whether this change is due to slowing of the cell cycle, as occurs during development, or to loss of precursor cells. In the current study, we find that the cell cycle time of granule cell precursors in middle-aged male rats is not significantly different from that in young adults. The size of the precursor pool, however, was 3-4 times smaller in the middle-aged rats, as determined using both cumulative bromodeoxyuridine (BrdU) labeling as well as labeling with the endogenous marker of cell proliferation, proliferating cell nuclear antigen (PCNA). Loss of precursor cells was much greater in the granule cell layer than in the hilus, suggesting that dividing cells in the hilus belong to a distinct population, most likely glial progenitors, that are less affected by aging than neuronal precursors. BrdU-labeled precursor cells and young neurons, labeled with doublecortin, appeared to be lost equally from rostral and caudal, as well as suprapyramidal and infrapyramidal, subregions of the granule cell layer. However, doublecortin staining did show large parts of the caudal granule cell layer with few if any young neurons at both ages. Taken together, these findings indicate that precursor cells are not distributed evenly within the dentate gyrus in adulthood but that precursors are lost from throughout the dentate gyrus in old age with no concomitant change in the cell cycle time.