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Neurogenesis persists throughout life under normal and degenerative conditions. The adult subventricular zone (SVZ) generates neural stem cells capable of differentiating to neuroblasts and migrating to the site of injury in response to brain insults. In the present study, we investigated whether estradiol increases neurogenesis in the SVZ in an animal model of stroke to potentially promote the ability of the brain to undergo repair. Ovariectomized C57BL/6J mice were implanted with capsules containing either vehicle or 17beta-estradiol, and 1 week later they underwent experimental ischemia. We utilized double-label immunocytochemistry to identify the phenotype of newborn cells (5-bromo-2'-deoxyuridine-labeled) with various cellular markers; doublecortin and PSA-NCAM as the early neuronal marker, NeuN to identify mature neurons, and glial fibrillary acidic protein to identify astrocytes. We report that low physiological levels of estradiol treatment, which exert no effect in the uninjured state, significantly increase the number of newborn neurons in the SVZ following stroke injury. This effect of estradiol is limited to the dorsal region of the SVZ and is absent from the ventral SVZ. The proliferative actions of estradiol are confined to neuronal precursors and do not influence gliosis. Furthermore, we show that both estrogen receptors alpha and beta play pivotal functional roles, insofar as knocking out either of these receptors blocks the ability of estradiol to increase neurogenesis. These findings clearly demonstrate that estradiol stimulates neurogenesis in the adult SVZ, thus potentially facilitating the brain to remodel and repair after injury.

Estrogen receptor-alpha (ER-alpha) and ER-beta exhibit fine differences in their distributions in the rodent forebrain, and one such difference is observed in the paraventricular (PVN) and supraoptic (SON) nuclei. To investigate the functional significance of ER in these brain areas, we examined the neuropeptide characteristics of ER-expressing neurons in the PVN and SON of female rats by using dual-label immunocytochemistry. The distributions of ER-alpha immunoreactivity (ir) and ER-beta ir were nonoverlapping in the PVN and SON. Nuclear ER-alpha ir was found in a population of thyrotropin-releasing hormone (TRH)-expressing neurons in the PVN (5.93% +/- 1.20% SEM), but not in any other identified cell phenotype of the PVN and SON. The phenotype of neurons with the highest percentage expressing ER-beta was found to be prolactin (PRL) immunoreactive in both the parvocellular (84.95% +/- 4.11%) and the magnocellular (84.76% +/- 3.40%) parts of the PVN as well as the SON (87.57% +/- 4.64%). Similarly, most vasopressin-immunoreactive neurons were also ER-beta positive in the PVN (66.14% +/- 2.47%) and SON (72.42% +/- 4.51%). In contrast, although a high percentage of oxytocin (OXY) neurons coexpressed ER-beta in the PVN (84.39% +/- 2.99%), there was very little ER-beta/OXY colocalization in the SON. Low levels of corticotropin-releasing hormone neurons also expressed ER-beta ir in the PVN (12.57% +/- 1.99%), but there was no ER-beta colocalization with TRH. In summary, these findings further support the possibility of direct effects of estrogen on neuropeptide expression and implicate estrogen involvement in the regulation of various aspects of neuroendocrine function., (Copyright 2005 Wiley-Liss, Inc.)