Short-Term Estradiol Administration in Aging Ovariectomized Rats Provides Lasting Benefits for Memory and the Hippocampus: A Role for Insulin-Like Growth Factor-I

We previously demonstrated that aged ovariectomized rats that had received prior estradiol treatment in middle age exhibited enhanced spatial memory and increased levels of estrogen receptor (ER)-alpha in the hippocampus long after estradiol treatment was terminated. The implication for cognition of increased levels of ER alpha resulting from prior estradiol exposure is unknown. In the absence of estrogens, growth factors, including IGF-I, can induce ER alpha-mediated transcription through ligand-independent mechanisms. Our current goal was to determine whether IGF-I mediates the ability of short-term exposure to estradiol to exert long-term effects on cognition and the hippocampus of aging females. Ovariectomized middle-aged rats were implanted with estradiol or cholesterol vehicle capsules. After 40 days, all capsules were removed and drug treatments were initiated. Half of each hormone treatment group received chronic intracerebroventricular delivery of the IGF-I receptor antagonist JB1, and the other half received artificial cerebrospinal fluid vehicle. Rats were tested on a spatial memory radial-arm maze task and hippocampi were immunostained for proteins of interest by Western blotting. As expected, previous treatment with estradiol enhanced spatial memory and increased levels of ER alpha in the hippocampus. JB1 reversed these effects. Previous treatment with estradiol resulted in lasting increases in levels of IGF-I receptors and phosphorylation of ERK/MAPK, a downstream signaling molecule of both ER alpha and IGF-I receptors, and increased levels of the ER alpha-regulated protein, choline acetyltransferase. JB1 blocked effects on ERK/MAPK and choline acetyltransferase. Results indicate that activation of IGF-I receptors is necessary for prior estradiol exposure to exert lasting impact on the hippocampus and memory. (Endocrinology 154: 842-852, 2013)