SGER: 17alpha-estradiol: a novel endogenous mitogen and anti-depressant in the brain

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Functional adaptation of the brain throughout life centers around its ability to reorganize itself through the formation of new neural connections made possible by interactions with environmental stimuli. Such stimuli include changing levels of circulating hormones, such as the estrogen 17beta-estradiol, and androgens, such as testosterone, that can be converted enzymatically to 17beta-estradiol. It is generally accepted that 17beta-estradiol is the estrogen most active in the brain, while its little studied isomer, 17alpha-estradiol, a chemical compound with the same number and type of each atom but in a different arrangement, is generally considered biologically inactive. New data suggests that this viewpoint may be inaccurate and the role of this 17-alpha-estradiol in the nervous system needs to be re-evaluated. Accumulating evidence indicates that 17alpha-estradiol, unlike 17beta-estradiol which is of ovarian origin, is actually synthesized in the brain and may be critical for neural functions such as neurogenesis [new neuron formation through cell division] in the adult hippocampus, a brain region implicated in learning, memory and regulation of mood. It appears that 17alpha-estradiol is significantly higher in the brains of adult mice of both sexes than that of 17beta-estradiol, as determined by mass spectrometry, which determines the structure of a molecule or compound by fragmenting it into its component parts. The role of 17alpha-estradiol in the brain has remained largely unknown. Using cultures of brain cells and intact mice from mouse strains with either very low or elevated brain levels of 17alpha-estradiol, the roles of 17alpha-estradiol, 17beta-estradiol and sesame oil will be compared with respect to (i) neurogenesis, (ii) interactions with the growth factor BDNF (brain-derived neurotrophic factor), and (iii) ability to control moods. Completion of this research will provide a picture of how 17alpha-estradiol and sesame oil may act in the brain and how these hormones impact learning and memory and influence mood. This research will enable collaborations across disciplines with cell and molecular biologists, neuroscientists and biochemists. Training for undergraduate, graduate, and post-graduate research assistants (including underrepresented minorities and women) will be an integral aspect of the project. This project will also train future faculty, who are not yet independent faculty members themselves to obtain valuable teaching and mentoring skills by supervising less experienced researchers and undergraduate students.