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Mechanism of Estradiol Action in the Developing Brain
Stuart K. Amateau
School of Medicine, University of Maryland, Baltimore
Estrogen exposure has profound effects on the developing and adult brain, inducing widespread alterations ranging from the modification of gene expression through changes in behavior. In the menopause transition, ovarian steroid production is gradually inhibited and around a third of all women will seek medical help for postmenopausal symptoms. The hot flash is a characteristic manifestation occurring in the vast majority of women and is strongly associated with estrogen withdrawal and subsides with estrogen-based hormone replacement therapy. Although the exact pathophysiology of the flashes remains unknown, they are thought to be a disorder of thermoregulation initiated centrally within the preoptic area of the hypothalamus. If differentiation in circuitry underlies sex differences in behavior and physiology, the POA would be apt to display sexual dimorphisms. Astrocytes are important in synapse formation and efficacy, including that of estradiol-induced dendritic spine synapses. Recent and emerging evidence implicates prostaglandin-E2 (PGE2) as a mediator of dynamic cell-to-cell communication involving cross talk between astrocytes and neurons.
We have determined that as early as the day of birth, the morphology of astrocytes within the POA are sexually dimorphic and this difference is mediated by early exposure to the gonadal hormone estradiol (E2). These findings have led to the following testable hypotheses; (1) E2 binds neuronal estrogen receptors (ER) to (2) induce the release of neuronal PGE2, and (3) it is this crucial signaling molecule that initiates the differentiation of neighboring astrocytes. These hypotheses will be tested by the following experiments; cellular localization of the ER by double label immunocytochemistry, examination of the genes E2 regulates for the de novo synthesis of PGE2, by quantitative RT-PCR, and the assessment of the influence of in vivo pharmacologic treatments of PGE2on developing astrocytes by morphometric analysis.
