Estrogen and glucocorticoid receptors (ER and GR) are both members of the same subfamily of steroid nuclear receptors, and can both signal classically as ligand-activated transcription factors. However, many responses to estrogen and glucocorticoid exposure occur through the non-classical pathways, which include rapid activation of kinase cascades, activation of membrane-associated receptors, gene regulation through transcription by non-classical transcription factors, and protein regulation by translation and post-translational modification. Male territorial aggression is a hypothalamically-mediated steroid hormone-dependent adaptive behavior in mice. The hypothalamus, which expresses multiple ERs and GRs, is also responsive to estrogen and glucocorticoid treatment at a cellular level. Experiments were conducted to test the effects of estrogen and glucocorticoid interactions on spinogenesis in the ventromedial hypothalamus (VMH) and on male territorial aggression through the resident-intruder paradigm. Studies in male postnatal primary hypothalamic cell cultures demonstrate the expression of classic ERα, the variant ERα-36, and GPR30. PSD-95 protein, a marker for dendritic spines, is increased in response to 12 hours of treatment with the GPR30 agonist G-1 in an ERK/MAPK-dependent manner. Further work in immortalized embryonic hypothalamic cell lines (mHypoE-11 and mHypoE-42) demonstrate non-classical effects of a membrane-limited glucocorticoid on rapid nuclear translocation of the intracellular GR. Additionally, pharmacological inhibition of the ERK/MAPK pathway results in similar GR translocation in the absence of a ligand. Male postnatal primary hypothalamic cell cultures also respond to glucocorticoid exposure with increased 17Î_-E synthesis, suggesting crosstalk between GR signaling and estrogen signaling. Spine density in the gonadally intact adult male VMH decreases following suppression of estrogen synthesis with the aromatase inhibitor letrozole, suggesting estrogen is necessary to maintain spine density. In vivo studies in adult male mice demonstrate that estrogen is necessary to maintain basal peripheral CORT synthesis. Behavior testing using the resident-intruder paradigm showed that dexamethasone-suppression of adrenal CORT synthesis increases the amount of time resident mice spent engaged in aggressive bouts, and CORT treatment 20 minutes prior to aggression testing abolished this effect. The findings presented here provide support for the importance of the interactions between classical and non-classical estrogen and glucocorticoid signaling pathways on hypothalamic spinogenesis and male territorial aggression. / 1 / Jennifer Rainville
| Identifer | oai:union.ndltd.org:TULANE/oai:http://digitallibrary.tulane.edu/:tulane_45924 |
| Date | January 2015 |
| Contributors | Rainville, Jennifer R. (author), Vasudevan, Nandini (Thesis advisor), School of Science & Engineering Cell and Molecular Biology (Degree granting institution) |
| Source Sets | Tulane University |
| Language | English |
| Detected Language | English |
| Type | Text |
| Format | electronic |
| Rights | No embargo |
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