acase@tulane.edu / The goal of the following experiments was to determine the cellular mechanisms through which estrogen receptor activity is maintained in hippocampal cells following termination of ovarian function. Aim 1 determined that kinase signaling contributes to the maintenance of estrogen receptor activity in the hippocampus of ovariectomized mice in addition to local synthesis of brain derived “neuroestrogens”. Inhibition of both the mitogen activated protein kinase (MAPK) and phosphoinositide-3 kinase (PI3K) cascades with intracerebroventricular infusion of specific kinase inhibitors reduced estrogen response element (ERE)-dependent gene expression in the hippocampus of ovariectomized mice. Aim 2 determined that neuroestrogen synthesis, MAPK signaling, and PI3K signaling interact to regulate the transcriptional output of estrogen receptors in response to insulin like growth factor-1 receptor (IGF-1R) activation in the Neuro-2A cell culture model. Rapid IGF-1R-dependent MAPK signaling promotes, while PI3K signaling inhibits, IGF-1R-dependent activation of endogenous estrogen receptors in Neuro-2A cells. Long-term IGF-1R stimulation reduces ERE-dependent gene expression in part through phosphorylation of estrogen receptor alpha (ERα). Rapid IGF-1R-dependent activation but not long-term repression of estrogen receptor activity in Neuro-2A cells requires neuroestrogen synthesis. Aim 3 determined that exposure to 40 days of continuous unopposed estradiol at the time of ovariectomy results in lasting enhancement of estrogen receptor activity in the hippocampus and lasting enhancement of hippocampus dependent memory in female mice beyond the period of short-term estradiol exposure. Together these three aims determine that neuroestrogen synthesis and kinase signaling interact to actively maintain estrogen receptor signaling in neuronal cells and these autonomous neuronal mechanisms of estrogen receptor activation have functional consequences on cognition long after cessation of ovarian function. / 1 / Kevin J Pollard
| Identifer | oai:union.ndltd.org:TULANE/oai:http://digitallibrary.tulane.edu/:tulane_76927 |
| Date | January 2017 |
| Contributors | Pollard, Kevin (author), Daniel, Jill (Thesis advisor), School of Science & Engineering Neuroscience (Degree granting institution) |
| Publisher | Tulane University |
| Source Sets | Tulane University |
| Language | English |
| Detected Language | English |
| Type | Text |
| Format | electronic, 175 |
| Rights | No embargo, Copyright is in accordance with U.S. Copyright law. |
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