Menopause is characterized as a state of reproductive senescence coincident with sharply decreased circulating estrogen levels. Recently, the women's health initiative (WHI) conducted a large-scale clinical study designed to evaluate the neurological benefits of estrogen replacement therapy for post-menopausal women. The results of that study, combined with other studies using animal models, have sparked a fervent debate about whether estrogen is beneficial or detrimental to normal brain function. Estrogen signaling in the brain is conveyed by two high specificity receptors, estrogen receptors alpha and beta (ER1, ER2). Data from our laboratory have focused on the biological function of ER2 for two neuronal-specific genes that are estrogen-responsive and dramatically altered as a direct result of the aging process: gonadotropin-releasing hormone (GnRH) and arginine vasopressin (AVP). GnRH is the primary central regulator of reproduction and AVP is a critical regulator of several processes including mood, circadian rhythms, and the stress response. Our data demonstrate that ER2 differentially regulates these genes in the presence and absence of estrogen, leading to our central hypothesis that the basic function of ER2 in the brain changes during the aging process. Understanding the molecular basis and the associated underlying consequences of changes in ER2 signaling is critical for evaluating the efficacy and necessity of exogenous hormone therapies. The activity of estrogen-bound ER2 can be modulated by different mechanisms, including posttranslational modifications of the receptor, recruitment of coregulatory proteins into the transcription complex, or binding to unique cis-acting promoter elements on the target genes. Whether the estrogen-independent activation of AVP and GnRH by ER2 is mediated by one or all of these mechanisms is unknown.
The specific aims outlined in this proposal will investigate each of these possibilities using a variety of molecular biology techniques in neuronal cells. The expected results will further our understanding of ER2 signaling in the post-menopausal brain by elucidating the precise molecular mechanisms that drive estrogen-independent regulation of ER2 target genes.

Public Health Relevance

During normal aging, there is a sharp decline in circulating estrogen levels. The positive health benefits of estrogen replacement therapy in the aged brain have gained considerable interest in recent years;however, our understanding of the molecular mechanisms regulating estrogen signaling in neurons is limited. This proposal will investigate the consequences of estrogen-independent gene regulation in neurons, which is imperative to understand in order to critically evaluate the efficacy and necessity of exogenous hormone therapies.

National Institute of Health (NIH)
National Institute on Aging (NIA)
Research Project (R01)
Project #
Application #
Study Section
Aging Systems and Geriatrics Study Section (ASG)
Program Officer
Mackiewicz, Miroslaw
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Loyola University Chicago
Anatomy/Cell Biology
Schools of Medicine
United States
Zip Code
Rao, Yathindar S; Pak, Toni R (2016) microRNAs and the adolescent brain: Filling the knowledge gap. Neurosci Biobehav Rev 70:313-322
Shults, Cody L; Pinceti, Elena; Rao, Yathindar S et al. (2015) Aging and Loss of Circulating 17β-Estradiol Alters the Alternative Splicing of ERβ in the Female Rat Brain. Endocrinology 156:4187-99
Pinceti, E; Shults, C L; Rao, Y S et al. (2015) Phosphorylation Alters Oestrogen Receptor β-Mediated Transcription in Neurones. J Neuroendocrinol 27:861-71
Rao, Yathindar S; Shults, Cody L; Pinceti, Elena et al. (2015) Prolonged ovarian hormone deprivation alters the effects of 17β-estradiol on microRNA expression in the aged female rat hypothalamus. Oncotarget 6:36965-83
Mott, Natasha N; Pinceti, Elena; Rao, Yathindar S et al. (2014) Age-dependent Effects of 17β-estradiol on the dynamics of estrogen receptor β (ERβ) protein-protein interactions in the ventral hippocampus. Mol Cell Proteomics 13:760-79
Tajuddin, Nuzhath F; Przybycien-Szymanska, Magdalena M; Pak, Toni R et al. (2013) Effect of repetitive daily ethanol intoxication on adult rat brain: significant changes in phospholipase A2 enzyme levels in association with increased PARP-1 indicate neuroinflammatory pathway activation. Alcohol 47:39-45
Pak, Toni R; Rao, Yathindar S; Prins, Sarah A et al. (2013) An emerging role for microRNAs in sexually dimorphic neurobiological systems. Pflugers Arch 465:655-67
Rao, Yathindar S; Mott, Natasha N; Wang, Yanru et al. (2013) MicroRNAs in the aging female brain: a putative mechanism for age-specific estrogen effects. Endocrinology 154:2795-806
Mott, N N; Pak, T R (2012) Characterisation of human oestrogen receptor beta (ERýý) splice variants in neuronal cells. J Neuroendocrinol 24:1311-21
Przybycien-Szymanska, Magdalena M; Mott, Natasha N; Paul, Caitlin R et al. (2011) Binge-pattern alcohol exposure during puberty induces long-term changes in HPA axis reactivity. PLoS One 6:e18350

Showing the most recent 10 out of 11 publications