Newly born cells migrate long distances and are incorporated into functional neural circuits in the adult brain. This can occur in more than one brain area, including the high vocal center (HVC) of songbirds (Alvarez-Buylla, Arturo, & Kirn, 1997; Barnea & Nottebohm, 1994), and in the hippocampus in songbirds and mammals (Altman & Das, 1965), where these new neurons can potentially alter behavior. Although sex steroids have a moderate effect on the generation of neurons in the subventricular zone (Brown, Johnson, & Bottjer, 1993), androgens and estrogens likely influence the survival of neurons (Hidalgo, Barami, Iversen, & Goldman, 1995). Importantly, the modulation of neurogenesis by sex steroids involves chronic effects by androgens and estrogens and relatively recent demonstrations of the rapid effects of estrogens.
Fluctuations of circulating androgens and estrogens can influence neurogenesis via effects on proliferation, migration, and/or survival. Castrated male rats demonstrate decreases in the survival of newly born cells in the hippocampus, an effect reversed by injections of testosterone or the nonaromatizable androgen DHT. In contrast, the administration of estradiol does not appear to rescue castration-dependent decreases in hippocampal cell survival, suggesting a role for androgens, but not estrogens, in this effect (Spritzer & Galea, 2007). Similarly, testosterone implants increase cell survival in the HVC of canaries (Serinus canarius) (Rasika, Nottebohm, & Alvarez-Buylla, 1994) and European starlings (Sturnus vulgaris) (Absil, Pinxten, Balthazart, & Eens, 2003). These effects can involve multiple cell-signaling systems, as demonstrated by the fact that in the canary, testosterone-mediated increases in neuronal survival appear to be brain-derived neurotrophic factor (BDNF) dependent (Rasika, Alvarez-Buylla, & Nottebohm, 1999). The data suggest that in both birds and mammals, androgens may exert potent effects on many aspects of adult neurogenesis.
Estrogens also have been implicated in the regulation of cell proliferation and survival in the adult vertebrate brain. Adult female rats generate more neurons in the hippocampus than do males (Gould, Beylin, Tanapat, Reeves, & Shor, 1999), and females in estrus have higher levels of cell proliferation compared to those in diestrus (Tanapat, Hastings, Reeves, & Gould, 1999). These differences appear to be estradiol dependent, as administration of this steroid to ovariectomized rats increases the number of new cells in the hippocampus compared to ovariectomized females injected with control injection alone (Tanapat et al., 1999). These effects have also been demonstrated in vitro, as treatment of hippocampal cultures with an aromatase inhibitor decreases proliferation relative to controls, an effect reversed by coadministration of estradiol (Fester, Ribeiro-Gouveia, Prange-Kiel, & Rune, 2006). Interestingly, estradiol can also affect neurogenesis in the adult male brain. Castrated males that are administered estradiol have increased cell survival compared to controls in meadow voles (Ormerod, Lee, & Galea, 2004) and prairie voles (Smith, Pencea, Wang, Luskin, & Insel, 2001).
Although much work focuses on the chronic effect (i.e., greater than 24 hours) of sex steroids on neurogenesis, emerging evidence demonstrates that some aspects of this modulation may occur more rapidly. Short-term exposure (2–4 hours), but not long-term exposure (2–3 days), to estradiol increased survival of neurons in the female vole (Ormerod & Galea, 2001; Ormerod, Lee, & Galea, 2003). Similarly, administration of estradiol for 3 days does not alter either hippocampal proliferation or survival in female voles (Fowler, Freeman, & Wang, 2003). These effects suggest that estradiol’s effects may be more rapid than previously appreciated.
Similar to rodents, the growth of brain nuclei in songbirds is also potently affected by estrogens. Soma, Tramontin, Featherstone, and Brenowitz (2004) treated wild adult male song sparrows (Melospiza melodia) with an aromatase inhibitor either with or without estradiol replacement in breeding and nonbreeding conditions. In breeding males, aromatase inhibition resulted in a decrease in the volume of HVC, an effect partially rescued by concomitant estradiol treatment. In nonbreeding birds, estradiol increased the volume of HVC within two weeks, suggesting that the aromatization of circulating androgens to estrogens may be important modulators of adult neuroplasticity in this species (Soma et al., 2004).
