The goal of the current experiments was to assess the role of estrogen receptor alpha (ERë±) in the ability of a prior, short-term exposure to estradiol in mid-life to enhance cognition and affect the hippocampus in aging, ovariectomized rats, as well as to investigate a possible mechanism involving the insulin-like growth factor-1 system by which ERë± may exert these effects. In Experiment 1, rats were trained on the radial maze, ovariectomized, and implanted with estradiol or cholesterol vehicle capsules for 40 days. Rats then continuously received JB1 or aCSF vehicle i.c.v. and were tested on delay trials on the radial maze. Using Western blotting, I determined effects of treatment on protein levels of ERë±, ChAT, IGF-1R, IGF-1BP2, and phosphorylated and total p42/p44 MAPK and Akt in the hippocampus. Antagonism of IGF-1 receptors blocked the ability of prior estradiol exposure to enhance cognition and increase ERë±, phosphorylated ERK/MAPK, and ChAT in the hippocampus. The second experiment was divided into two parts. In Experiment 2A, rats were trained on the radial maze and ovariectomized. After 40 days, rats underwent stereotaxic surgery to receive lentiviral delivery of the gene encoding for ERë± or control virus to the hippocampus, and were then tested on delay trials. Using Western blotting, I determined if proteins of interest previously found to be affected by a prior exposure to estradiol in Experiment 1 would be affected by treatments for all subsequent experiments. Lentiviral delivery of ERë± to the hippocampus was sufficient to enhance cognition and increase phosphorylation of ERK/MAPK in the hippocampus. In Experiment 2B, rats were trained on the radial maze, ovariectomized, and implanted with estradiol or cholesterol vehicle capsules for 40 days. Rats then continuously received an ER antagonist or aCSF vehicle i.c.v. and were tested on delay trials. Antagonism of ERë± blocked the ability of prior estradiol exposure to enhance cognition. In the third experiment, rats were trained on the radial maze, ovariectomized, and implanted with estradiol or cholesterol vehicle capsules for 40 days. Rats then underwent stereotaxic surgery to receive i.c.v. cannula. Infusion of an ERK/MAPK inhibitor or aCSF vehicle was administered every 12 hours during delay trials. Inhibition of ERK/MAPK did not block the ability of prior estradiol exposure to enhance cognition, although it did block an increase in levels of ERë± in the hippocampus. Altogether, these results indicate that ERë± plays an important role in the ability of prior estradiol exposure to enhance cognition and affect the hippocampus in aging, ovariectomized rats, and likely interacts with the IGF-1 system and its associated ERK/MAPK signaling pathway. / acase@tulane.edu
| Identifer | oai:union.ndltd.org:TULANE/oai:http://digitallibrary.tulane.edu/:tulane_26553 |
| Date | January 2013 |
| Contributors | Witty, Christine F. (Author), Daniel, Jill (Thesis advisor) |
| Publisher | Tulane University |
| Source Sets | Tulane University |
| Language | English |
| Detected Language | English |
| Rights | Copyright is in accordance with U.S. Copyright law |
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