Diversity of mechanisms involved in aromatase regulation and estrogen action in the brain

in Biochimica et Biophysica Acta - General Subjects (2010)

Background In recent years, the mechanisms through which estrogens modulate neuronal physiology, brain morphology, and behavior have proven to be far more complex than previously thought. For example, a ... [more ▼]

Background In recent years, the mechanisms through which estrogens modulate neuronal physiology, brain morphology, and behavior have proven to be far more complex than previously thought. For example, a second nuclear estrogen receptor has been identified, a new family of coregulatory proteins regulating steroid-dependent gene transcriptions was discovered and, finally, it has become clear that estrogens have surprisingly rapid effects based on their actions on cell membranes, which in turn result in the modulation of intracellular signaling cascades. Scope of review This paper presents a selective review of new findings in this area related to work in our laboratories, focusing on the role of estrogens in the activation of male sexual behavior. Two separate topics are considered. We first discuss functions of the steroid receptor coactivator-1 (SRC-1) that has emerged as a key limiting factor for behavioral effects of estradiol. Knocking-down its expression by antisense oligonucleotides drastically inhibits male-typical sexual behaviors. Secondly, we describe rapid regulations of brain estradiol production by calcium-dependent phosphorylations of the aromatase enzyme, themselves under the control of neurotransmitter activity. These rapid changes in estrogen bioavailability have clear behavioral consequences. Increases or decreases in estradiol concentrations respectively obtained by an acute injection of estradiol itself or of an aromatase inhibitor lead within 15–30 min to parallel changes in sexual behavior frequencies. These new controls of estrogen action offer a vast array of possibilities for discrete local controls of estrogen action. They also represent a formidable challenge for neuroendocrinologists trying to obtain an integrated view of brain function in relation to behavior. [less ▲]

Effects of estrogen receptors alpha and beta agonists on the sexual behavior and the neuroplasticity in male Japanese quail.

Poster (2010)

Own song selectivity in the songbird auditory pathway: suppression by norepinephrine

Poster (2010)

Steroid receptor coactivator 2 (SRC-2) mediates steroid-dependent male sexual behavior and neuroplasticity in Japanese quail (Coturnix japonica).

Poster (2010)

Sex steroid-induced neuroplasticity and behavioral activation in birds

in European Journal of Neuroscience (2010), 32

Rapid regulation of aromatase activity and the role of stress

Poster (2010)

Who's in charge? Nuclear receptor coactivator function in brain and behavior

Scientific conference (2009)

Quand Valentin rencontre Valentine: Hommes-Femmes Mode d'emploi. Introduction Biologique

Scientific conference (2009)

Temporal change in the expression of steroid receptor coactivator (SRC-1) and coactivator-associated arginine methyltransferase (CARM-1) in new cells of the dentate gyrus of adult female rats.

Poster (2009)

Importance of steroid receptor coregulators for neuronal phenotype determination: Modulation of steroid action

in Trabajos del Instituto Cajal (2009), LXXXII

Steroid receptors such as estrogen receptors alpha and beta and androgen receptors are transcription factors involved in the transcriptional regulation of a large number of target genes. Steroid-dependent ... [more ▼]

Steroid receptors such as estrogen receptors alpha and beta and androgen receptors are transcription factors involved in the transcriptional regulation of a large number of target genes. Steroid-dependent expression in the brain controls a large array of biological processes including spatial cognition, copulatory behavior and neuroprotection. The discovery of a competition, or squelching, between two different nuclear receptors introduced the notion that common cofactors might be involved in the modulation of transcriptional activity of nuclear receptors. These cofactors, which are now known as coactivators, are involved in chromatin remodeling and stabilization of the general transcription machinery. Since the characterization of the steroid receptor coactivator 1 or SRC-1, more than 100 different cofactors have been identified. Although an increasingly large amount of information has been collected about the in vitro function of these coregulatory proteins, relatively little is known regarding their physiological role in vivo, particularly in the brain. Our laboratory and others have demonstrated the importance of SRC-1 in the differentiation and activation of steroid-dependent sexual behaviors and the related neural genes. In Japanese quail, the inhibition of SRC-1 expression by intracerebroventricular antisense injections blocked the activating effects of exogenous testosterone on male sexual behaviors and the steroid-dependent vasotocine expression and increase of the median preoptic area volume defined by Nissl staining as well as by aromatase immunoreactivity. These data therefore strongly suggested that SRC-1 is required to modulate estrogen receptor dependent gene-expression. It is however interesting to note that steroid receptors and SRC-1 are not always colocalized. For example, both glial cells and neurons in the hippocampus express estrogen receptor alpha but SRC-1 is rarely observed in glia. It is therefore possible that estrogen receptor alpha in glial cell require another coactivator or set of coactivators to induce estrogen-dependent gene transcription. It has been suggested very recently that SRC-1 is associated with neuronal differentiation of neural stem cell derived from the ganglionic eminence of mouse embryos. These stem cells differentiating into glial cell (GFAP-positive) did not express SRC-1. The presence of a specific coactivator could therefore determine a specific cell phenotype (neuronal vs glial). Another coactivator, the coactivator-associated arginine methyl transferase 1 or CARM-1 seems to be important to keep progenitor cells in a dividing state. The inhibition of CARM-1 expression leads to neuronal differentiation. Neurogenesis can therefore offers an excellent model to define the spatio-temporal role of different coactivators. It is indeed possible to study a subset of coactivators associated to various stages phenotype determination (proliferation vs. differentiation). The study of neurogenesis in the dentate gyrus of the hippocampus in female adult rats shows that around 40 % of proliferative cells express SRC-1 or CARM-1. Interestingly, 70% of proliferative cells express SRC-1 but only a very few cells (<5%) express CARM-1. We are currently investigating the temporal pattern of expression of these two coactivators during the neurogenesis in the hilus and dentate gyrus. The expression of the coactivators CARM-1 and SRC-1 is analyzed in proliferating and differentiating cells. We expect that proliferating and differentiating cells will differentially express the two coactivators. It seems that the presence of a precise subset of coactivators could help defining the phenotype of the cell by modulating a specific downstream pathway after steroid receptor activation. The very large number of coactivators and their association into preformed complexes potentially allows the determination of hundreds of different phenotypes. The study of the expression of the coactivator and their function in vivo is required to fully understand steroid action and specificity in the brain. [less ▲]