Estradiol enhances neurogenesis following ischemic stroke through estrogen receptors α and β

Abstract

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 Enhances Neurogenesis and Behavioral Recovery after Stroke

“…Stroke-induced neurogenesis was again higher in ovary intact randomly cycling females (IF) compared with oil-treated ovx females and no different than that seen in E2-supplemented ovx females (intact; 36.8±4.2 versus ovx females 23 ± 3.9, data not shown). In agreement with previous work (Suzuki et al, 2007) and as in the dSVZ, supplementation of physiological levels of E2 did not affect the basal proliferation of neurons or astrocytes in sham-operated mice in the DG ( Figures 2A and 2C), suggesting the proliferative effect of E2 is limited to ischemic brain.…”

“…The ERa-and ERb-positive cells have been identified in the ventricular wall of both embryonic and adult rat brain and mRNA for both ERa and ERb are present in the dentate gyrus (DG) (Merchenthaler et al, 2004). Both ERa and ERb appear to contribute to early cell proliferation (e.g., 72 hours) after stroke in mice (Suzuki et al, 2007), but whether these cells survive past 3 days or if there were corresponding changes in functional recovery is not known. As the peak of stroke-induced neurogenesis occurs well after this period (Kuge et al, 2009), we aimed to (1) evaluate the effect of E2 on stroke-induced neurogenesis in the male and female brain, (2) assess maturation and long-term survival of newborn cells, (3) determine whether E2-induced neurogenesis led to enhanced behavioral recovery, and finally (4) determine whether classical ERs or aromatase has a role in mechanisms by which E2 induces neurogenesis.…”

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

“…Interestingly, in mice, the invalidation of ER␤ involves a regional neuronal hypocellularity especially in the cerebral cortex and an abnormal migration of new neurones. This suggest that ER␤ has an important role in brain development by influencing migration and neuronal survival (Wang et al, 2001Suzuki et al, 2007). In agreement, it was recently demonstrated that estradiol induces human neural progenitor cell proliferation through an estrogen receptor beta-phosphorylated extracellularly regulated kinase pathway .…”

Testosterone and estradiol differentially affect cell proliferation in the subventricular zone of young adult gonadectomized male and female rats

“…On the contrary, a short-term exposure to E 2 negatively affects cell proliferation in C57Bl6/J female mice SVZ (Brock et al, 2010). Interestingly, in OVX female mice of the same strain, a chronic treatment with low doses of E 2 stimulates cell proliferation in the SVZ of post-stroke animals, although such increase was not present in control animals (Suzuki et al, 2007). In rats, a chronic treatment with E 2 on OVX females results in a minor number of newborn neurons integrating in the accessory OB (Hoyk et al, 2006), however, in this study neurogenesis was evaluated only at long survival time after BrdU injection, thus it is not clear if this is an effect on cell proliferation or on cell survival.…”

“…In the SVZ neurogenic niche such studies have been mostly performed in females by specifically focusing on the effect of E 2 in both naïve and neurodegenerative models (Saravia et al, 2004, Hoyk et al, 2006, Suzuki et al, 2007, Brock et al, 2010, Veyrac and Bakker, 2011. Only indirect evidences indicate that other gonadal hormones, such as progesterone and T can regulate neurogenesis in the adult SVZ niche (Peretto et al, 2001, Giachino et al, 2004, Zhang et al, 2010, Tatar et al, 2013.…”