Prolonged ovarian hormone deprivation alters the effects of 17β-estradiol on microRNA expression in the aged female rat hypothalamus

Administration of 17β-estradiol (E(2)) has beneficial effects on cognitive function in peri- but not post-menopausal women, yet the molecular mechanisms underlying age-related changes in E(2) action remain unclear. We propose that there is a biological switch in E(2) action that occurs coincident with age and length of time after ovarian hormone depletion, and we hypothesized that age-dependent regulation of microRNAs (miRNAs) could be the molecular basis for that switch. Previously we showed that miRNAs are regulated by E(2) in young compared to aged female rats. Here we tested whether increasing lengths of ovarian hormone deprivation in aged females altered E(2) regulation of these mature miRNAs. In addition, we determined where along the miRNA biogenesis pathway E(2) exerted its effects. Our results showed that age and increased lengths of ovarian hormone deprivation abolished the ability of E(2) to regulate mature miRNA expression in the brain. Further, we show that E(2) acted at specific points along the miRNA biogenesis pathway.