RT Journal Article SR Electronic T1 Circulating estradiol regulates brain-derived estradiol via actions at GnRH receptors to impact memory in ovariectomized rats JF eneuro JO eneuro FD Society for Neuroscience SP ENEURO.0321-16.2016 DO 10.1523/ENEURO.0321-16.2016 A1 Nelson, Britta S. A1 Black, Katelyn L. A1 Daniel, Jill M. YR 2016 UL http://www.eneuro.org/content/early/2016/12/02/ENEURO.0321-16.2016.abstract AB Systemic estradiol treatment enhances hippocampus-dependent memory in ovariectomized rats. Although these enhancements are traditionally thought to be due to circulating estradiol, recent data suggest these changes are brought on by hippocampus-derived estradiol, the synthesis of which depends on gonadotropin-releasing hormone (GnRH) activity. The goal of the current work is to test the hypothesis that peripheral estradiol affects hippocampus-dependent memory through brain-derived estradiol regulated via hippocampal GnRH receptor activity. In Experiment 1, intracerebroventricular infusion of letrozole, which prevents the synthesis of estradiol, blocked the ability of peripheral estradiol administration in ovariectomized rats to enhance hippocampus-dependent memory in a radial-maze task. In Experiment 2, hippocampal infusion of antide, a long-lasting GnRH receptor antagonist, blocked the ability of peripheral estradiol administration in ovariectomized rats to enhance hippocampus-dependent memory. In Experiment 3, hippocampal infusion of GnRH enhanced hippocampus-dependent memory, the effects of which were blocked by letrozole infusion. Results indicate that peripheral estradiol-induced enhancement of cognition is mediated by brain-derived estradiol via hippocampal GnRH receptor activity.Significance Statement Results of years of research have demonstrated that circulating estradiol, the main estrogen produced by the ovaries, impacts memory and the hippocampus. More recently data have revealed that the brain can synthesize its own estradiol, the release of which also impacts the hippocampus. The relationship between the ability of circulating estradiol and brain-derived estradiol to impact the hippocampus and hippocampus-dependent memory is unclear. Here we demonstrate that the impact of circulating estradiol on memory is mediated by brain-derived estradiol through mechanisms involving gonadotropin-releasing hormone (GnRH). These data have significance for understanding mechanisms by which loss of ovarian hormones can impact memory.