Ovariectomized rats that received previous administration of oestradiol in midlife display enhanced cognition and increased hippocampal levels of oestrogen receptor alpha (ERα) months after oestradiol treatment ended as compared to ovariectomized controls. Objectives of the current work were to investigate mechanisms by which ERα levels are maintained following midlife oestradiol exposure and the role of ERα in memory in aging females in the absence of circuiting oestrogens. Unliganded ERα has increased interaction with the ubiquitin ligase, C terminus of Hsc-70 interacting protein (CHIP) leading to increased degradation of the receptor. In our first experiment, we tested the hypothesis that midlife oestradiol exposure in ovariectomized rats results in decreased interaction between CHIP and hippocampal ERα, leading to increased levels of ERα. Middle-aged rats were ovariectomized and received oestradiol or vehicle implants. After 40 days, implants were removed. One month later, rats were killed and hippocampi processed for whole protein western blotting and co-immunoprecipitation, in which ERα was immunoprecipitated from lysate. As expected, ERα protein expression was increased in rats previously treated with oestradiol compared to vehicle-treated rats. In rats treated with oestradiol, there was a decrease in CHIP-ERα interaction, suggesting that previous oestradiol treatment reduces interaction, slowing degradation of ERα. In a second experiment, we determined the impact on memory of antagonism of ER in the absence of circulating oestrogens. Rats were ovariectomized and implanted with oestradiol capsules. Capsules were removed after 40 days. Rats received chronic i.c.v. infusion of ER antagonist, ICI 182,780 or aCSF vehicle and were tested on a spatial memory radial maze task. Rats treated with ICI 182,780 had significantly worse performance (more errors). These experiments provide evidence that previous midlife oestradiol treatment maintains hippocampal ERα by decreasing its interaction with CHIP and that activation of these receptors provides cognitive benefits in the absence of circulating oestrogens.

No abstract

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 the first experiment, 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 the second experiment, 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 the third experiment, 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.

We previously demonstrated that 40 days of prior midlife estradiol treatment results in enhanced spatial memory in aging ovariectomized rats long after termination of the estradiol treatment. Our current goal was to determine whether this benefit is due to lasting impacts on memory specifically of previous exogenous estradiol treatment or simply due to delaying cognitive deficits that occur following loss of ovarian hormones. Middle-aged rats were ovariectomized or underwent sham surgery. Ovariectomized rats received estradiol (Previous Estradiol) or vehicle (Previous Vehicle) implants. Rats undergoing sham surgery (Previous Intact) received vehicle implants. Forty days later, Previous Intact rats were ovariectomized, the other 2 groups underwent sham surgeries, and all implants were removed. Thus, no ovarian or exogenously administered hormones were present during behavior testing. Rats underwent 24 days of acquisition training on an 8-arm radial maze. Following acquisition and again 2 months later, rats were tested on delay trials, during which animals had to remember the location of food rewards across time delays inserted between fourth and fifth arm choices. During acquisition, rats that had previous extended exposure to exogenous estradiol (Previous Estradiol) and endogenous ovarian hormones (Previous Intact) significantly outperformed rats that did not experience extended hormone exposure (Previous Vehicle). However, during delays trials the Previous Estradiol group significantly outperformed both the Previous Vehicle and Previous Intact groups. Results demonstrate that whereas extended exposure to endogenous ovarian hormones may provide short-term cognitive benefits, midlife estradiol treatment following ovariectomy provides additional benefits that persist for months following termination of treatment. (PsycINFO Database Record (c) 2018 APA, all rights reserved).