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

Abstract

Administration of 17β-estradiol (E₂) has beneficial effects on cognitive function in peri- but not post-menopausal women, yet the molecular mechanisms underlying age-related changes in E₂ action remain unclear. We propose that there is a biological switch in E₂ 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 E₂ in young compared to aged female rats. Here we tested whether increasing lengths of ovarian hormone deprivation in aged females altered E₂ regulation of these mature miRNAs. In addition, we determined where along the miRNA biogenesis pathway E₂ exerted its effects. Our results showed that age and increased lengths of ovarian hormone deprivation abolished the ability of E₂ to regulate mature miRNA expression in the brain. Further, we show that E₂ acted at specific points along the miRNA biogenesis pathway.