Different Forms of Oestrogen Rapidly Upregulate Cell Proliferation in the Dentate Gyrus of Adult Female Rats

Abstract

Oestrogens are known to exert significant structural and functional effects in the hippocampus of adult rodents. The dentate gyrus of the hippocampus retains the ability to produce neurones throughout adulthood and 17beta-oestradiol has been shown to influence hippocampal neurogenesis in adult female rats. The effects of other oestrogens, such as oestrone and 17alpha-oestradiol, on neurogenesis have not been investigated. The present study aimed to investigate the effects of 17beta-oestradiol, oestradiol benzoate, oestrone, and 17alpha-oestradiol on cell proliferation in ovariectomised adult female rats at two different time points. Young ovariectomised female rats were injected with one of the oestrogens at one of three doses. In Experiment 1, rats were exposed to the hormone for 4 h and, in Experiment 2, rats were exposed to the hormone for 30 min prior to 5-bromo-2-deoxyuridine injection to label proliferating cells and their progeny. We found that young ovariectomised females responded with increased cell proliferation to most oestrogens, except oestradiol benzoate, after 30 min of exposure. However, administration of oestrogens for a longer time interval was ineffective at increasing cell proliferation. After 30 min, 17beta-oestradiol and oestrone increased cell proliferation at low (0.3 microg) and high (10 microg) doses, whereas 17alpha-oestradiol increased cell proliferation at medium (1 microg) and high doses. The results of the present study indicate that different oestrogens rapidly increase cell proliferation in a dose-dependent manner, possibly through a nonclassical, nongenomic mechanism. Future experiments should focus on further elucidating the specific pathways utilised by each oestrogen. These results have important therapeutic implications because it may be possible to use 17alpha-oestradiol and lower doses of oestrogens in hormone replacement therapies.

Early regulation of brain aromatase (cyp19a1b) by estrogen receptors during zebrafish development

“…The meaning of these observations is still subject to speculation, but growing evidence now suggests that production of estrogens by radial glial cells could be important in the context of embryonic or adult neurogenesis (Garcia-Segura et al, 2001; Martinez- Cerdeno et al, 2006;Galea, 2008;Barha et al, 2009;De Nicola et al, 2009;Mouriec et al, 2009). In addition, there is substantial evidence in fish showing that cyp19a1b expression is strongly up-regulated by estrogens and aromatizable androgens Halm et al, 2002;Menuet et al, 2005;Le Page et al, 2006, 2008Mouriec et al, 2009).…”

“…In other vertebrates, including teleost fish, radial cells persit in adult (Onteniente et al, 1983;Menuet et al, 2003Menuet et al, , 2005Zupanc and Clint, 2003;Pellegrini et al, 2007) and it was recently shown that radial cell can generate neurons throughout adult life in fish Adolf et al, 2006). The role of aromatase in radial glial cells is poorly understood, but estrogens are now strongly suspected to participate in the process of embryonic, adult or reparative neurogenesis (Garacia-Segura et al, 2001;Martinez-Cerdeno et al, 2006;Galea, 2008;Mouriec et al, 2008;Barha et al, 2009;De Nicola et al, 2009;Kimmel et al, 1995).…”

Low Doses of 17α-Estradiol and 17β-Estradiol Facilitate, Whereas Higher Doses of Estrone and 17α- and 17β-Estradiol Impair, Contextual Fear Conditioning in Adult Female Rats

“…Given that ERs in the brain show tissue and region-specific patterns of expression (Shughrue et al, 1997), and the diverse behaviors they regulate (Kudwa et al, 2006;Rhodes and Frye, 2006), it is plausible that different forms of estrogen could have profound and distinct effects on neural plasticity and/or behavior. Despite the fact that estrone is centrally active (Barha et al, 2009) and is the main component of the HRT Premarin, to our knowledge only one study has directly examined the effects of estrone on learning (Farr et al, 2000). Thus, in this study we sought to determine whether there were differential effects of the estrogens, estradiol, and estrone, on contextual fear conditioning.…”

“…These doses were chosen based on earlier studies investigating spatial learning and hippocampal neurogenesis (Tanapat et al, 1999;Ormerod et al, 2003;Holmes et al, 2002;Tanapat et al, 2005;Barha et al, 2009). A high dose of 10 mg 17b-estradiol was chosen because it results in circulating levels of estradiol observed on the morning of proestrus (Viau and Meaney, 1991) and has been shown to enhance cell proliferation 30 min (Barha et al, 2009), 2 h (Tanapat et al, 1999;Tanapat et al, 2005), and 4 h (Ormerod et al, 2003;Barha et al, 2009) after injection. However, this same dose produces supraphysiological levels of estradiol shortly after administration (Woolley and McEwen, 1993).…”

“…Although 17b-estradiol binds to ERa and ERb with an approximately 40-fold higher affinity, 17a-estradiol (Perez et al, 2005) may be the preferred ligand of ER-X, a plasma membrane-associated ER (Toran-Allerand et al, 2002). In addition, 17a-estradiol has been shown to affect the structure and function of the hippocampus by rapidly increasing spine density in the CA1 region of the hippocampus (Maclusky et al, 2005), enhancing place memory (Rhodes and Frye, 2006;Luine et al, 2003), and increasing cell proliferation in the dentate gyrus of adult female rats (Barha et al, 2009). Therefore, it is possible that 17a-estradiol could have effects on hippocampus-dependent contextual fear conditioning.…”