SUN-469 Hypothalamic ERalpha Gene Silencing Diminishes Sexual Receptivity in Female Marmoset Monkeys

Abstract

Estradiol (E2) has long been established as a major regulator of female sexual behavior in mammals, including primates. Estrogen receptor alpha (ERαλπηα) in the ventromedial nucleus of the hypothalamus (VMN) has been identified as the major molecular gateway facilitating sexually receptive behavior in rodents. In primates, however, a role for ERalpha or any other estrogen receptor in female sexual motivation has not been identified. We hypothesized that eliminating expression of ERαλπηα in the VMN of female marmoset monkeys would result in diminished female receptivity. Female marmosets were ovariectomized (OVX) and received E2 replacement therapy, and assigned to one of two hypothalamic infusion treatments: (1) control, scrambled shRNA, and (2) selective ERαπηα protein depletion with ERα gene silencing shRNA. MRI-guided neural infusion surgery enabled delivery of appropriate shRNA. Co-expression of green fluorescent protein (GFP) was used to visualize localization of transduced neurons. At least 6 mo following treatment onset, female monkeys were observed in six 30-min behavioral testing sessions with their male partner. Brain tissue was perfused and analyzed by immunohistochemistry to quantify accuracy and effectiveness of gene silencing using NIS-elements computer software. ERαλπηα gene silencing shRNA successfully diminished ERαλπηα protein expression in the VMN (p=0.04). Additionally, in the E2-replaced, ERα gene silenced females, sexually receptive behaviors were decreased compared with E2 replaced controls (p<0.001). Interestingly, the decreased receptivity was not accompanied by increased sexual rejection. Together, these findings demonstrate that ERαλπηα activation in the VMN is an obligate component of the neural mechanisms governing female sexual receptivity in a non-human primate.