Date of Award

2020

Degree Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Department

Physiology

Abstract

In females, levels of estrogens fluctuate across the lifespan and rapidly decline during menopause. Hormone replacement therapy (HRT) has been introduced as a clinical alternative to replenish systemic levels of 17β-estradiol (E2), the primary estrogen in circulation. However, studies from the Women's Health Initiative revealed a critical period immediately following the onset of menopause where HRT is efficacious. Here, we identified the differential regulation of miRNAs, small non-coding RNAs that inhibit translation, as a potential mechanism for this temporal switch in estrogen action. Specifically, early - but not late - E2 administration following ovariectomy in a rat model of menopause stabilized miR-9-3p, a critical neuronal miRNA that governs neuronal differentiation and synaptic plasticity. This estrogen-mediated stability was specific to miR-9-3p, as its complementary strand, miR-9-5p, was unaffected. Furthermore, we found that the subcellular localization of these two miRNAs can also be regulated by E2 both to the nucleus and to specific RNA binding proteins (RBPs). Given miR-9-3p's role in governing neuronal homeostasis, the estrogen-mediated regulation of miR-9-3p is an attractive mechanism to underlie the disparate effects of HRT in the aging female brain.

Creative Commons License

Creative Commons License
This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 3.0 License.

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