Abstract
Neurogenesis of dentate gyrus granule cells is generally considered to be negatively regulated by glucocorticoids. We tested the hypothesis that exposure to low plasma corticosteroid levels starting in the early postnatal period enhances granule cell proliferation rate during adulthood. Rat pups were adrenalectomized (ADX) on postnatal day 10 and were then "clamped" throughout life at low corticosterone levels via oral supplementation. Neurogenesis was determined using BrdU immunochemistry at 3 and 12 months in clamped rats as compared with age-matched, sham-operated controls. Rate of neurogenesis did not differ between the groups at either 3 or 12 months. It was significantly lower in 12-month-old compared with 3-month-old rats, despite the presence of an age-dependent increase of plasma corticosterone only in the sham-ADX rats. Granule cell layer volume, granule cell density, and granule cell degeneration (determined using apoptotic markers) were indistinguishable in the two groups, further supporting the comparable rate of neurogenesis under differing chronic glucocorticoid levels. In addition, whereas acute deprivation of plasma glucocorticoids (adrenalectomy) in adult rats evoked a burst of granule cell neurogenesis, complete elimination of these hormones (by stopping hormone supplementation) in adult, early-life ADX/clamped rats did not. These data do not support a simple inverse relationship between chronic plasma glucocorticoid levels and granule cell neurogenesis. Specifically, chronic modulation of glucocorticoid levels commencing early in life evokes additional, adaptive, and compensatory mechanisms that contribute to the regulation of granule cell proliferation.
Highlights
In mammalian brain, the dentate gyrus (DG) is among the few areas where production of significant numbers of new neurons continues throughout life (Altman and Das, 1965; Bayer et al, 1982; Kuhn et al, 1996; Eriksson et al, 1998; Kornack and Rakic, 1999)
If glucocorticoid levels determine the rate of neurogenesis in the aging hippocampus, granule cell production should be significantly increased in chronically clamped rats when compared with age-matched controls
The major findings of these experiments are: (1) lifelong exposure to low plasma glucocorticoids, when commencing early in life, does not lead to chronic increase of granule cell neurogenesis; (2) hippocampal granule cell production correlates inversely with age in both intact and ADX/clamped animals, suggesting that aging-related reduction of neurogenesis is not governed exclusively by glucocorticoids; (3) the neurogenic potential of granule cells in response to total deprivation of corticosteroids is lost when low plasma steroid levels are imposed starting early in life; and (4) increased MR levels and loss of GR regulation by plasma glucocorticoids may contribute to the adaptation of granule cell neurogenesis to lifelong low plasma levels of these hormones
Summary
The dentate gyrus (DG) is among the few areas where production of significant numbers of new neurons continues throughout life (Altman and Das, 1965; Bayer et al, 1982; Kuhn et al, 1996; Eriksson et al, 1998; Kornack and Rakic, 1999). During aging (> 12 months), plasma CORT reaches its highest levels (e.g., Sapolsky, 1992; but see Heine et al, 2004), whereas granule cell production decelerates further (Kuhn et al, 1996; Nichols et al, 2001; Bizon and Gallagher, 2003; but see Heine et al, 2004) This intriguing correlation of plasma glucocorticoids and granule cell neurogenesis has led to the hypothesis that elevated glucocorticoid levels are responsible for decreased neurogenesis in the aging hippocampus (Cameron and McKay, 1999; Drapeau et al, 2003). If glucocorticoid levels determine the rate of neurogenesis in the aging hippocampus, granule cell production should be significantly increased in chronically clamped rats when compared with age-matched controls
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