The Dentate Gyrus

The subhilar region of the dentate gyrus is a specialized proliferative population that produces the granule cells of the dentate gyrus. The presence of a proliferating population of stem and progenitor cells in the dentate gyrus of mammals was first described in the mouse (Angevine, 1964, 1965). This proliferating population initially arises from the VZ of the medial wall of the lateral ventricle, that is, near the anlage of the dentate gyrus, and migrates into the future position of the dentate hilus (Nowakowski and Rakic, 1981). It persists there during the developmental period and even throughout adulthood in all mammals studied including rodents (Kaplan and Hinds, 1977; Bayer, 1982; Bayer et al., 1982; Stanfield and Trice, 1988), monkeys (Kornack and Rakic, 1999), and humans (Eriksson et al., 1998). Despite the persistence of this proliferative population into adulthood, the vast majority of the output of this proliferative population occurs between birth and P20, during which time approximately 80% of the neurons and glial cells of the murine dentate gyrus are born (Angevine, 1965; Bayer and Altman, 1975). However, there is also evidence that in the adult this pro-liferative population continues to give rise to neurons (and glia), some portion of which survive, migrate into the granule cell layer, form connections, and become a permanent part of the dentate gyrus granule cell layer (Bayer, 1982; Bayer et al., 1982; Crespo et al., 1986; Stanfield and Trice, 1988) and exhibit important functional properties (van Praag et al., 2002). Importantly, it has been shown that during the adult period the number of granule cells increases (Bayer, 1982; Bayer et al., 1982), the newly produced granule cells displace earlier generated granule cells (Crespo et al., 1986), and they grow an axon into the molecular layer of CA3 (Stanfield and Trice, 1988). In recent years, this proliferative population has been studied as an example of postnatal neurogenesis and stem cell proliferations. Proliferation in the subhilar region of the dentate gyrus has been shown to be affected by genetic differences (Kempermann et al., 1997; Hayes and Nowakowski, 2002), species differences (Kornack and Rakic, 1999), various treatments such as drugs (Eisch et al., 2000), stress (Tanapat et al., 1998; Gould and Tanapat, 1999), behavioral experiences (Kempermann et al., 1998a), hormones (Cameron et al., 1998; Tanapat et al., 1999), aging (Kempermann et al., 1998b), and exercise (van Praag et al., 1999).

Although proliferation in the dentate gyrus persists throughout the life span of the animal, there is a significant decline with age (Kuhn et al., 1996; Kempermann et al., 1998b); in mice at 18 months of age the reported number of BUdR labeled cells observed after 12 daily injections is only about 25% of the number observed after a similar labeling paradigm at 6 months of age (Kempermann et al., 1998b). This decline could be due to a decrease in the number of proliferating cells, an increase in the amount of cell death (in either the proliferating population or the output population) during the 12-day period during which the BUdR injections were given, or both. (However, as yet untested is the possibility that the difference could be a result of changes in Tc and/or Ts with age, for example, by a lengthening of G1 or a shortening of S.) What is significant, however, is that the proliferation continues even in aged animals and that even though there is a large decline over a one-year period, the decline is relatively small when considered with respect to the length of a single cell cycle, which is about 12-14 hr in mice (Hayes and Nowakowski, 2002) and about 24 hr in rats (Cameron and McKay, 2001). Using the longer cell cycle, that is, ~24 hr, the changes due to age would indicate that the size of the proliferating population declines at a rate of <0.15% per cell cycle. (Note that the converse also would hold; that is, if the proliferating population is in fact a constant size, then an increase in the length of the cell cycle of —0.15% per cell cycle could account for the age changes.)

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