The window and mechanisms of major age-related decline in the production of new neurons within the dentate gyrus of the hippocampus

Aging Cell. 2006 Dec;5(6):545-58. doi: 10.1111/j.1474-9726.2006.00243.x.

Abstract

While it is well known that production of new neurons from neural stem/progenitor cells (NSC) in the dentate gyrus (DG) diminishes greatly by middle age, the phases and mechanisms of major age-related decline in DG neurogenesis are largely unknown. To address these issues, we first assessed DG neurogenesis in multiple age groups of Fischer 344 rats via quantification of doublecortin-immunopositive (DCX+) neurons and then measured the production, neuronal differentiation and initial survival of new cells in the subgranular zone (SGZ) of 4-, 12- and 24-month-old rats using four injections (one every sixth hour) of 5'-bromodeoxyuridine (BrdU), and BrdU-DCX dual immunostaining. Furthermore, we quantified the numbers of proliferating cells in the SGZ of these rats using Ki67 immunostaining. Numbers of DCX+ neurons were stable at 4-7.5 months of age but decreased progressively at 7.5-9 months (41% decline), 9-10.5 months (39% decline), and 10.5-12 months (34% decline) of age. Analyses of BrdU(+) cells at 6 h after the last BrdU injection revealed a 71-78% decline in the production of new cells per day between 4-month-old rats and 12- or 24-month-old rats. Numbers of proliferating Ki67+ cells (putative NSCs) in the SGZ also exhibited similar (72-85%) decline during this period. However, the extent of both neuronal differentiation (75-81%) and initial 12-day survival (67-74%) of newly born cells was similar in all age groups. Additional analyses of dendritic growth of 12-day-old neurons revealed that newly born neurons in the aging DG exhibit diminished dendritic growth compared with their age-matched counterparts in the young DG. Thus, major decreases in DG neurogenesis occur at 7.5-12 months of age in Fischer 344 rats. Decreased production of new cells due to proliferation of far fewer NSCs in the SGZ mainly underlies this decline.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Aging / physiology*
  • Animals
  • Bromodeoxyuridine
  • Cell Count
  • Cell Differentiation / physiology*
  • Cell Proliferation*
  • Cell Survival / physiology
  • Dentate Gyrus / cytology
  • Dentate Gyrus / physiology*
  • Immunohistochemistry
  • Ki-67 Antigen / metabolism
  • Male
  • Microtubule-Associated Proteins / metabolism
  • Models, Biological
  • Neurons / cytology
  • Neurons / metabolism*
  • Neuropeptides / metabolism
  • Rats
  • Rats, Inbred F344
  • Stem Cells / cytology
  • Stem Cells / metabolism*
  • Telencephalon / cytology
  • Telencephalon / physiology

Substances

  • Ki-67 Antigen
  • Microtubule-Associated Proteins
  • Neuropeptides
  • doublecortin protein
  • Bromodeoxyuridine