Title: Molecular Aspects of the Regulation of Female Sexual Behavior

Copyright Information: All rights reserved unless otherwise indicated. Contact the author or original publisher for any necessary permissions. eScholarship is not the copyright owner for deposited works. Learn more at The regulation of female sexual receptivity by estradiol is complex and requires both the classical nuclear receptors and membrane estrogen receptors. It is only through the combined actions of both of these types of receptors in the brain and peripheral tissues that the female is ready for sexual behavior. The nuclear receptors dimerize, bind to DNA and regulate transcription, and thereby the translation of new proteins. The membrane estrogen receptors exert their effects through another method. In the arcuate nucleus of the hypothalamus (ARH), hippocampus and striatum, estrogen receptor-α (ERα), the only estrogen receptor shown to be required for sexual receptivity, transactivates metabotropic glutamate receptors (mGluRs) in order to initiate G protein signaling. This leads to the phosphorylation of a diverse array of signaling molecules depending upon which mGluR is activated. In a membrane to nucleus iii signaling schema, membrane-initiated estradiol signaling can lead to the activation of cAMP response element binding protein (CREB), which also in turn affects transcription. For the activation of sexual receptivity, the association of ERα with mGluR1a, leading to the phosphorylation of PKCθ, is required in the ARH. In the present set of experiments, I show that three other events within the ARH are necessary for sexual receptivity: caveolin-1 (CAV1) mediated ERα trafficking, spinogenesis, and modulation of activity regulated cytoskeleton associated protein (Arc). Estradiol regulates levels of membrane ERα modulating its own signaling, and CAV1 is a scaffold protein that traffics receptors to the membrane. In vitro, it has been observed to move ERα and the ERα-mGluR1 complex to the membrane. Without this protein, signaling in these neurons was significantly attenuated. Until now, no work had been done to examine whether CAV1-mediated ERα trafficking is involved in the activation of sexual receptivity in vivo. siRNA directed against CAV1 was used to knock down CAV1 protein in the ARH. This led to a significant reduction in membrane ERα, circuit activation and sexual receptivity. Estradiol-mediated spinogenesis has been seen in several areas of the brain related to sexual receptivity including the ventromedial hypothalamus (VMH), which is considered the final common output from the limbic-hypothalamic lordosis behavior regulating module. Increases in dendritic spine density in the VMH and ARH have been proposed to regulate this behavior, but there …