Loss of libido is a significant medical problem and results in a profound diminution of life and many patient visits to the urologist. In part, male sexual drive requires the synthesis of testosterone mediated by the steroidogenic acute regulatory (StAR) protein in testicular Leydig cells. Interestingly, the enzymes responsible for steroidogenesis in the Leydig cell are also present in neuronal and glial cell types of the brain. This leads to the intriguing possibility that steroids locally produced in the brain (neurosteroids) could be involved in the regulation of libido, as well. In fact, administration of neurosteroids in the brain has been shown to affect sexual behavior in rodents. Therefore, we plan to investigate whether hormone-regulated neurosteroids are critical for libido. Recently, mRNA encoding the hormone-regulated StAR protein, was detected in the brain. This gives us an exciting chance to more directly assess the functional role of neurosteroids by developing a model whereby we eliminate StAR protein expression and thus, steroid production in the brain, without affecting steroid synthesis in the gonads and the adrenal gland. Selectivity will be accomplished by using a Cre-lox tissue-specific knockout strategy. We propose to use this model to test the hypothesis that while gonadal steroids are permissive, StAR-dependent neurosteroid synthesis in the brain has an essential physiologic role in libido. Therefore, to test the hypothesis that StAR-mediated neurosteroid synthesis is essential for libido, I propose to both define the pathways involved in neurosteroid biosynthesis in the brain (especially in structures important for libido) and the regulation of StAR by immunohistochemisry, in vitro assays, and other biochemical techniques, and to generate a conditional StAR-knockout mouse model to examine effects on the brain and sexual behavior during and after development and in aging.
