localized modulation of testosterone action: Function of steroid receptor coactivators in the brain

Testosterone, through its activation of androgen and estrogen receptors, has been shown to play a critical role in brain development and physiology. Recent studies have shown that the activity of these receptors can be modulated by the interaction with several proteins and, in particular, that coactivators are required to enhance their transcriptional activity. The steroid receptor coactivator-1, SRC-1 is the best-characterized coactivator and we review here the current knowledge on the distribution, regulation of expression and function of this protein in the brain, focusing mostly on our work in Japanese quail. As expected for a ubiquitous coactivator, SRC-1 is present throughout the brain in both mammalian and avian species but is found in particularly high concentrations in testosterone-sensitive areas such as the preoptic area in rat and Japanese quail and in the song control nuclei in songbirds. Further analysis demonstrates that the expression of SRC-1 is not constitutive but regulated in specific brain areas by the sex, acute stress and testosterone treatment. In addition, the protein concentration appears to fluctuate through the day in some brain regions. These modulations of SRC-1 expression by endogenous (sex) and exogenous (stress) factors could potentially exacerbate at specific times the competition or squelching between different nuclear receptors and therefore decrease the biological response induced by one or another hormonal system. Although the existence of such a phenomenon has not yet been demonstrated in a functionally intact biological system, the effects of SRC-1 antisense treatments clearly strengthen this hypothesis. Indeed, the decrease of SRC-1 expression in the hypothalamus induced by antisense oligonucleotide injections clearly inhibited both estrogen-dependent male sexual behavior and androgen-dependent pre- and post-copulatory displays (strut) in Japanese quail, therefore demonstrating a role of the coactivator in the transcriptional activation induced by both estrogen and androgen receptors. Interestingly, the inhibitory effect on sexual behavior of SRC-1 knock down was not systematically associated with modifications of several histological (definition of median preoptic nucleus [POM] using Nissl staining), immunohistochemical (aromatase and vasotocin cells and fibers in the POM) and biochemical (aromatase enzymatic activity) markers of testosterone action in the brain. This dissociation of the effects of SRC-1 on behavior on the one hand and on aromatase and POM neurochemistry on another hand suggests that other system(s) involved in the activation of male sexual behavior are likely more sensitive to a decrease of SRC-1 expression. In future research, it will be essential to determine the other cofactors involved in specific physiological responses and to define whether these coactivators act synergistically, in parallel or independently in the modulation of the activity of one or several nuclear receptors linked to a particular physiological event. In several biological models, the observed changes in concentration of the circulating hormone and /or its receptors are apparently not sufficient to explain the physiological and behavioral responses observed after testosterone treatment. The discovery of steroid receptor coactivators opens new perspectives in the study of the molecular basis of steroid action at the level of the organism and a complete understanding of the mechanisms of steroid action will not be achieved without a detailed characterization of nuclear receptor cofactors