Previous estradiol treatment during midlife maintains transcriptional regulation of memory-related proteins by ERα in the hippocampus in a rat model of menopause

Previous midlife estradiol treatment, like continuous treatment, improves memory and results in lasting increases in hippocampal levels of estrogen receptor (ER) alpha and ER-dependent transcription in ovariectomized rodents. We hypothesized that previous and continuous midlife estradiol act to specifically increase levels of nuclear ER alpha, resulting in transcriptional regulation of proteins that mediate estrogen effects on memory. Ovariectomized middle-aged rats received estradiol or vehicle capsule implants. After 40 days, rats initially receiving vehicle received another vehicle capsule (ovariectomized controls). Rats initially receiving estradiol received either another estradiol (continuous estradiol) or a vehicle (previous estradiol) capsule. One month later, hippocampi were dissected and processed. Continuous and previous estradiol increased levels of nuclear, but not membrane or cytosolic ER alpha and had no effect on Esr1. Continuous and previous estradiol impacted gene expression and/or protein levels of mediators of estrogenic action on memory including ChAT, BDNF, and PSD-95. Findings demonstrate a long-lasting role for hippocampal ER alpha as a transcriptional regulator of memory following termination of previous estradiol treatment in a rat model of menopause. (C) 2021 The Author(s). Published by Elsevier Inc.