Emilie F. Rissman, PhD
Role of steroids, steroid receptors subtypes, and neuropeptides in behavior; behavioral effects of androgen ablation
Among US men prostate cancer is the most common cancer. A major part of the treatment regime for most prostate cancers is maintenance of the patient on anti-androgen therapy. One of the major quality of life issues associated with this therapy is loss of sexual interest, libido, and a decline in sexual performance. In this application a mouse model will be employed to replicate the hormonal treatments given to prostate patients. As in men, hybrid mice under similar treatment conditions show a range of behavioral responses. Specifically F1 hybrids produced by crossing two common mouse strains; C57BL/6J and DBA/2J can retain copulatory behavior, including ejaculations for up to two years after bilateral orchidectomy. They have replicated these findings and in addition demonstrated that copulatory behaviors persist despite both orchidectomy and treatment with the potent anti-androgen, flutamide. In this exploratory application they describe a novel research program that uses this mouse model to reveal the molecular genetic mechanisms that are responsible for this unique androgen-independent behavior. The Rissman lab will screen mice for the persistence of sexual interest after bilateral orchidectomy combined with flutamide treatment and select those that continue and those that do not persist in their sexual behavior. Next they will collect RNA from the essential neural region in the mouse brain that is responsible for sexual functioning, the medial preoptic area (POA). MicroArray analysis will be used to compare gene expression between these two mouse populations and candidate genes that vary to the greatest degree between the two populations will be studied further. Real Time PCR will be used to quantify mRNA in the mPOA, and western blotting to quantify the amount of protein for each candidate gene in brains of mice that continue versus those that stop mating. Finally candidate peptides will be infused with intracranial cannulation techniques to attempt to restore copulatory behavior in non-responsive males. This set of studies will expand their knowledge of substrates that underlie sexual behavior, which may lead to new approaches to anti-androgen treatment and greater quality of life for cancer survivors.