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Lasting Impact on Memory of Midlife Exposure to Exogenous and Endogenous Estrogens

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.