We previously demonstrated that aged ovariectomized rats that had received prior estradiol treatment in middle age exhib- ited enhanced spatial memory and increased levels of estrogen receptor (ER)-a in the hippocampus long after estradiol treat- ment was terminated. The implication for cognition of increased levels of ERa resulting from prior estradiol exposure is unknown. In the absence of estrogens, growth factors, including IGF-I, can induce ERa-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 cap- sules were removed and drug treatments were initiated. Half of each hormone treatment group received chronic intracerebro- ventricular 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 blot- ting. As expected, previous treatment with estradiol enhanced spatial memory and increased levels of ERa in the hippocam- pus. JB1 reversed these effects. Previous treatment with es- tradiol resulted in lasting increases in levels of IGF-I receptors and phosphorylation of ERK/MAPK, a downstream signaling molecule of both ERa and IGF-I receptors, and increased levels of the ERa-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.
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