The ovarian steroid hormones, estradiol and progesterone, regulate cellular functions in the central nervous system resulting in changes in physiology and reproductive behavior in a variety of species. Progesterone effects on sexual behavior are mediated not only through the """"""""classical"""""""" genomic mechanism of action involving the intracellular nuclear receptors, but also via rapid """"""""non-classical"""""""" pathways involving extra-nuclear signal transduction cascades. While the cellular and molecular mechanisms involved in the convergence of these two mechanisms are not well understood, it could involve """"""""cross-talk"""""""" between protein kinase-dependent signal transduction cascades initiated at the membrane and the nuclear transcription factors. Pronounced signal amplification achieved by the protein kinase cascades could alter phosphorylation dynamics within the neuronal cells to achieve additive, synergistic or redundant effects producing a multi-component, but coordinated molecular response, culminating in an unified behavioral outcome. This proposal focuses on the determination of the mechanisms of progesterone action that extend beyond the classical intracellular steroid receptor-mediated pathways. In particular, we propose to determine the biochemical and molecular events underlying the rapid progesterone-initiated signal transduction pathway(s).
Specific aim 1 will determine the mechanism underlying the rapid, progesterone-initiated signaling in areas associated with lordosis. We will test the hypothesis that the progesterone-initiated increases in cAMP activate mitogen activated protein kinase (MAPK) pathway in the hypothalamus and preoptic area (POA), the regions known to be associated with lordosis circuitry. We will determine whether activation of MAPK pathway results in the phosphorylation of downstream nuclear transcriptional targets like Ca+2/cAMP response element binding protein (CREB).
Specific aim 2 will determine the intracellular localization of the activated MAPK cascade by examining the distribution of p-MAPK and its down-stream effectors at the cellular level.
Specific aim 3 will test the hypothesis that the progesterone-activated MAPK-mediated cascade and its transcriptional targets mediate sexual behavior in vivo. Identification of such cross-talk signaling mechanisms will contribute to our understanding of the environmental and internal determinants of hormone-brain-behavior mechanisms.
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