ReviewEffects of estradiol in adult neurogenesis and brain repair in zebrafish☆
Highlights
►Radial glial cells act as progenitor cells in the brain of adult teleost fish. ►The estrogen-synthesizing enzyme (Aromatase B) is only expressed by radial glial cells. ►We study the role of estrogens in neurogenic processes in adult zebrafish. ►We examine the potential links between brain repair and aromatase/estrogens.
Introduction
Estrogens are steroid hormones that sustain important physiological functions and exert pleiotropic effects on many target organs such as the gonads, the cardiovascular system, the liver, the skeleton, and the nervous system (Bazer et al., 2010, Boonyaratanakornkit et al., 2007, Couse and Korach, 1999, Horner, 2009, Karasu et al., 2011, Le Roux and Reh, 1994, Matthews and Gustafsson, 2003, Mesiano et al., 2011, Pettersson and Gustafsson, 2001, Zakar and Mesiano, 2011). Estrogen synthesis is permitted by a key enzymatic complex that involves aromatase and a ubiquitous flavoprotein, the NADPH cytochrome P450 reductase (Simpson and Davis, 2001). The most physiologically active hormone of these pleiotropic signaling molecules is estradiol (E2). Estradiol is notably recognized as an important actor in the development of the nervous system through organizing effects on brain circuitry. In rodents, embryonic neurogenesis is correlated with a peak in aromatase activity in the brain, leading to a period of strong estradiol production that influences the sexual differentiation of brain structures (Lephart, 1996). These developmental effects modulate neuroendocrine functions and impact subsequent behaviors in adulthood (McCarthy, 2009, Phoenix et al., 1959, Smith et al., 2009, Wang et al., 2003). The powerful effects of E2 on brain plasticity and functioning in adult brains are also well documented (McCarthy, 2009, McEwen et al., 1995, Tsurugizawa et al., 2005, Woolley, 2007). Recent data also highlight the role of centrally or peripherally produced E2 in the modulation of neurogenic activity in adult vertebrates under physiological conditions. For example, several studies point to a role for E2 in the regulation of proliferation in the subventricular zone of the forebrain (Brock et al., 2010), and in the subgranular zone of the hippocampal dentate gyrus (Bowers et al., 2010, Mazzucco et al., 2006, Ormerod et al., 2004). A decrease in hippocampal neurogenesis is induced in ovariectomized female rodents, whereas treatment with exogenous E2 promotes proliferative capacity, resulting in an increased number of newly generated neurons in the dentate gyrus (Bowers et al., 2010, Ormerod and Galea, 2001, Tanapat et al., 1999). Estradiol is also known to participate in the control of cell migration (Fan et al., 2006, Wang et al., 2003) and/or differentiation/plasticity. Significant effects on synapse formation such as amplified growth, arborization of neural processes and dendrite spine formation have been shown as a result of E2 treatment (Brinton, 2009, Murakami et al., 2006, Murashov et al., 2004). Additionally, E2 modulates the survival of neuronal cells as shown in aromatase knock-out adult female rats that exhibit exaggerated spontaneous apoptosis in the frontal cortex compared to wild type animals (Wang et al., 2001). This study and others manipulating bcl2 expression emphasize the anti-apoptotic role of estrogens (Alkayed et al., 2001, Sasaki et al., 2006).
A wealth of data also points to a role for estrogens in brain repair. Estradiol powerfully protects the brain against damage caused by mechanical or chemical injury by activating multiple mechanisms. A possible action would be to promote neurogenesis and to decrease cell death, notably via the regulation of anti and pro apoptotic genes. In various models of lesion, the neuroprotective effects of E2 are associated with local production of the hormone mediated by an increase in aromatase mRNA and protein levels around the lesion (Garcia-Segura, 2008, Garcia-Segura et al., 1999, Peterson et al., 2001, Peterson et al., 2004, Saldanha et al., 2009). Under physiological conditions, the localization of aromatase is mostly restricted to neurons, yet after chemical or mechanical injury, de novo aromatase expression is reported in reactive astrocytes in mammals (Garcia-Segura et al., 1999) and in radial glial cells in birds (Peterson et al., 2004). In both models, the strong injury-induced expression of aromatase is associated with the onset of intense proliferative activity in the injured area, suggesting a relationship between estrogen production and neurogenesis, similar to what has been described in mammals during brain development (Lephart, 1996).
Compared to other vertebrates, the brain of teleost fishes exhibits several unique features that make teleosts interesting models in which to investigate the effects of estrogens in adult neurogenesis and brain repair (Diotel et al., 2010, Le Page et al., 2010, März et al., 2010, Pellegrini et al., 2007). First, the adult fish brain exhibits high levels of proliferative activity in many areas lining the ventricles, mostly in the forebrain (Adolf et al., 2006, Chapouton et al., 2007, Ekström et al., 2001, Grandel et al., 2006, Lam et al., 2009, März et al., 2010, Pellegrini et al., 2007, Zupanc, 2001). This intense neurogenic activity is linked to the persistence of radial glial cells (RGC) acting as neural progenitors (Lam et al., 2009, März et al., 2010, Pellegrini et al., 2007, Rothenaigner et al., 2011). In mammals, the role of radial glial cells in neurogenesis during development is now strongly established and several groups have demonstrated that these cells not only provide a scaffold for migration of newborn cells, but also themselves generate new neurons (Campbell and Gotz, 2002, Costa et al., 2010, Noctor et al., 2001, Noctor et al., 2002, Rowitch and Kriegstein, 2010). At the end of mammalian embryonic neurogenesis, radial glial progenitors transform into astrocytes, while radial glial cells persist in the adult brain in other vertebrate groups such as birds, amphibians (D'Amico et al., 2011) or fish, in which the brain keeps growing during adulthood (Lindsey and Tropepe, 2006).
A striking feature of the fish brain is strong aromatase activity resulting from the high expression of the cyp19a1b gene, one of the two duplicated aromatase genes in fish (Tchoudakova and Callard, 1998). This gene encodes aromatase B, a cerebral form of the enzyme (Forlano et al., 2001, Menuet et al., 2003, Menuet et al., 2005, Strobl-Mazzulla et al., 2008). The profound expression of aromatase B is associated with neurogenic areas and studies using PCNA (Proliferative Cell Nuclear Antigen) and/or BrdU immunohistochemistry have clearly demonstrated that most of the RGC that divide are aromatase positive (Diotel et al., 2011, Kah et al., 2009, Pellegrini et al., 2007). Last, but not least, unlike the mammalian brain in which regenerative capacities are limited, the fish brain exhibits exceptional regeneration potential after injury (Ayari et al., 2010, Becker and Becker, 2008, Kizil et al., 2011, Kroehne et al., 2011, März et al., 2011, Zupanc, 2009, Zupanc and Zupanc, 2006).
As shown above, data obtained in mammals and birds suggest a link between estrogen production in radial glial cells or astrocytes and proliferative activity of these cells in many situations (embryonic, adult, or reparative neurogenesis). The unique features of the fish brain, in particular the production of estrogens by radial glial progenitors, together with the well-known action of estradiol on cell fate, strongly suggest the existence of a functional link between these observations. We thus decided to investigate whether estradiol could be the factor that explains the maintenance of proliferative activity in adults and the regeneration capacity after lesions.
Section snippets
Ethics
This study was approved by the ethics committee CREEA (Comité Rennais d'Ethique en matière d'Expérimentation Animale) permit number EEA B-35-040. The zebrafish were kept, handled, and sacrificed in accordance with the European Union regulations concerning the protection of experimental animals.
Animals and brain dissection
All experiments were performed on 6 month-old male wild type adult zebrafish (Danio rerio, AB strain) housed in the zebrafish facility of the IFR 140 (INRA SCRIBE, Rennes) and maintained under standard
The estrogenic environment modulates proliferative activity in the forebrain of adult zebrafish
In order to evaluate the impact of estrogens on proliferative activity, we exposed fish to the aromatase inhibitor ATD (10− 6 M) during 15 days. As shown in Fig. 1A, the treatment with ATD led to a complete inhibition of aromatase activity in the brain of adult zebrafish, compared to control fish treated with EtOH. Gonadal aromatase activity is also totally inhibited by this treatment (data not shown). In agreement with the fact that estrogens strongly up-regulate cyp19a1b expression, ATD
Discussion
The first part of our study demonstrates that, under normal conditions, manipulating the estrogenic environment affects neurogenic activity in adult zebrafish. This work is the first to address this particular question, and the data obtained so far indicate that estradiol treatment decreases cell proliferation in several brain regions and possibly affects cell migration and survival, without affecting differentiation. We also confirmed that the telencephalon of adult zebrafish exhibits a strong
Acknowledgments
The ANR NEED (CES-2008-11) (to O.K. and F.B), the Post-Grenelle grant NEMO (to F.B. and O.K.) and a NSC Taiwan-CNRS France exchange program (to B.C.C. and O.K) supported this research. The outstanding assistance of the staff of the BIOSIT zebrafish facility (INRA, Laboratoire de Physiologie et Génomique des Poissons) was greatly appreciated. We thank Sara Powers for improving the English style.
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Funded by the European project no 222719 (LIFECYCLE to OK), the ANR NEED (CES 2008-011), the Post-Grenelle de l'Environnement NEMO to OK.