Confocal fluorescent micrographs showing the localization of ER(beta)-GFP in green and Actin in red expressed in the Hippocampus-derived HT22 cell line
Steroid hormones, such as estrogen, exert dramatic effects in the brain involving neuroendocrine regulation, autonomic function, and behaviors related to reproduction and cognition. In addition, estrogens have been shown to have neurotrophic and neuroprotective effects.
Dr. Dorsa's laboratory has for several years attempted to understand the cellular and molecular events which mediate the effects of steroids on gene transcription in brain neurons and glia. Data gathered in neuroblastoma cells, in primary neuronal cultures, and in the rat and mouse brain in vivo suggests that estrogen acts not only through the "classical" mechanism of action involving nuclear hormone receptor dimerization and binding to consensus hormone response elements, but also via "cross-talk" with other protein kinase-dependent signal transduction pathways such as protein kinase A, and the mitogen activated protein kinases. These studies test the hypothesis that estrogenic regulation of gene expression in vitro and in vivo is related to membrane initiated events.
The lab also investigates the relative roles of estrogen receptor-subtypes (ERα and the newly identified ERβ) in these responses. These studies indicate a mix of "classical" and protein kinase-dependent transcriptional actions. It is, thus, the combination of these effects that confer the dramatic effects of hormones such as estrogen on the brain involved in neuroendocrine regulation, reproductive behavior, as well as neurotropic effects in the developing and aging. The approach involves identification of signal transduction cascades which respond to estrogen via membrane estrogen receptors, determination of their ability to enhance transcription of certain genes, and profiling their sensitivity to estrogen receptor agonists and antagonists. The goal is to identify the importance of membrane-based steroid effects in modulating CNS function.