Sexual receptivity is induced by the activity of estradiol (the primary estrogen in the body) through complex mechanisms that involve multiple signaling strategies in the brain.  Using a rodent model, we have identified specific endogenous opioid circuits in the area of the hypothalamus that are rapidly activated by estradiol to transiently inhibit sexual
The GPCR/MOR internalization assay has allowed us to dissect the signaling pathways activated by estradiol.  For example, in the arcuate nucleus, estradiol acts on a membrane estrogen receptor-α (ERα) to transactivate a metabotropic glutamate receptor, which phosphorylates a protein kinase-θ dependent signaling cascade responsible for lordosis circuit
Estradiol also remodels the connectivity of the nuclei of the lordosis regulating circuitry. In the arcuate nucleus, estradiol induces dendritic spines, which are critical for estradiol-induced lordosis behavior.  The initial spinogenesis is mediated by the stimulation of membrane estrogen receptors that deactivate (phosphorylate) an actin depolymerizing
We have explored membrane-initiated estradiol signaling in several other systems, as well.  For example, in dorsal root ganglion cells, ATP acts as a nociceptive messenger.  In these cells, estradiol activates an ERα that is coupled to a metabotropic glutamate receptor that inhibits L-type voltage gated Ca2+ channels (VSCC) and attenuates the influx of
The brain is not only a site for ovarian steroid metabolism; it is also a site of sex steroid biosynthesis.  We have determined that estradiol from developing ovarian follicles stimulates the synthesis of progesterone in the hypothalamus, and this neuroprogesterone is necessary for the initiation of the LH surge.  Indeed, blocking steroidogenesis in the
A classical question in reproductive neuroendocrinology is, “What is the mechanism of estrogen positive feedback that stimulates the luteinizing hormone (LH) surge?”  This is a critical question in the field, since the LH surge triggers two central events in reproduction:  ovulation and formation of the corpus luteum (which produces progesterone in the
How does glial progesterone activate the neurons controlling GnRH neurons to induce the LH surge? Our working hypothesis is that kisspeptin-expressing neurons are activated by progesterone.  Kisspeptin neurons have estradiol-induced progesterone receptors and potently stimulate GnRH neurons.  We are currently examining the mechanism through which this glial
The estradiol-induced inhibition of lordosis is mediated by µ-opioid receptors (MOR) that respond to morphine and the endogenous neuropeptide β-endorphin.  In the arcuate nucleus of the hypothalamus, estradiol treatment causes synaptic release of neuropeptide Y onto POMC neurons that project to the medial preoptic nucleus and release β-endorphin to activate