| Budget Amount *help |
¥15,660,000 (Direct Cost: ¥14,400,000、Indirect Cost: ¥1,260,000)
Fiscal Year 2007: ¥5,460,000 (Direct Cost: ¥4,200,000、Indirect Cost: ¥1,260,000)
Fiscal Year 2006: ¥4,900,000 (Direct Cost: ¥4,900,000)
Fiscal Year 2005: ¥5,300,000 (Direct Cost: ¥5,300,000)
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| Research Abstract |
Neurosteroids, produced de novo in the brain, regulate learning and memory processes by acutely modulating the ion conductivity of neurotransmitter receptors in hippocampal neurons. The pathway of neurosteroidogenesis and the regulation mode of neuronal signal transmission have not been well-elucidated, especially for sex steroids and stress steroids. In the present study, we first demonstrated the synthesis of androgens and stress steroids in rat hippocampus with HPLC analysis. The dominant path for estrogen and androgen metabolism in the hippocampus is "testosterone dihysrotestosterone (DHT) →3α, 5α-androstanediol", and "progesterone→deoxycorticosterone→corticosterone (CORT)" for stress steroid metabolism. mRNA analysis revealed the presence of cytochromes P450c21, P4502D4, P45011β1 and P45011β2 in the hippocampus of adult rats. The concentrations of estradiol and CORT were estimated to be approx. 5 nM and 500 nM, respectively, with high-sensitive mass spectrometry analysis.
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xamined the acute effect of sex steroids and stress steroids on the signal transmission of hippocampal neurons with electrophysiological measurements. DHT was demonstrated to promote long-term depression (LTD) induced with NMDA application only in hippocampal CA3 region. Estradiol promoted LTD in CA1-3 and in dentate gyrus (DG), which might be mediated via classical estrogen receptor a (ERα) located in synaptic region. CORT was demonstrated to weaken the strength of LTP induced with tetanus stimulation in hippocampal neurons via classical glucocorticoid receptors (GRs). Estradiol was shown to have the `antagonizing'' effect to CORT-induced LTP depression, which was mediated via ERα and ERβ, and consequent ERK/MAPK signaling pathway.
Furthermore, the effects of sex steroids on hippocampal spinogenesis were examined in the present study. Spines were visualized with Lucifer Yellow injection into single neuron. Estradiol was demonstrated to induce the increase in the spine density in CA1 within 2 hr, whereas decreased that in CA3. The spine increase in CA1 was mainly due to the selective increase in thin type spine. Estrogen receptor ERα, but not ERβ, was observed to be responsible for these estradiol-induced spinogenesis, as judged from the spine analysis using ERα agonist and ERβ agonist. Less
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