The window and mechanisms of major age-related decline in the production of new neurons within the dentate gyrus of the hippocampus.
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.
Rao
Muddanna S
MS
Department of Surgery (Division of Neurosurgery), Duke University Medical Center, Durham, NC 27710, USA.
Hattiangady
Bharathi
B
Shetty
Ashok K
AK
D000375:Aging / Q000502:physiology*; D000818:Animals; D001973:Bromodeoxyuridine; D002452:Cell Count; D002454:Cell Differentiation / Q000502:physiology*; D049109:Cell Proliferation; D002470:Cell Survival / Q000502:physiology; D018891:Dentate Gyrus / Q000166:cytology / Q000502:physiology*; D000089622:Doublecortin Domain Proteins; D000089662:Doublecortin Protein; D007150:Immunohistochemistry; D019394:Ki-67 Antigen / Q000378:metabolism; D008297:Male; D008869:Microtubule-Associated Proteins / Q000378:metabolism; D008954:Models, Biological; D009474:Neurons / Q000166:cytology / Q000378:metabolism*; D009479:Neuropeptides / Q000378:metabolism; D051381:Rats; D011916:Rats, Inbred F344; D013234:Stem Cells / Q000166:cytology / Q000378:metabolism*; D013687:Telencephalon / Q000166:cytology / Q000502:physiology
C000714848:Dcx protein, rat; D000089622:Doublecortin Domain Proteins; D000089662:Doublecortin Protein; D019394:Ki-67 Antigen; D008869:Microtubule-Associated Proteins; D009479:Neuropeptides; D001973:Bromodeoxyuridine