NEUROENDOCRINE BASES OF REPRODUCTIVE BEHAVIOR

生殖行为的神经内分泌基础

基本信息

批准号：
2202234
负责人：
ANNE M ETGEN
金额：
$ 12.78万
依托单位：
ALBERT EINSTEIN COLLEGE OF MEDICINE
依托单位国家：
美国
项目类别：
财政年份：
1993
资助国家：
美国
起止时间：
1993-01-01 至 1997-12-31
项目状态：
已结题

项目摘要

If one accepts the view that behavior is the product of neuronal activity, then it is reasonable to examine the influence of hormones on brain cells in the neural circuits that mediate hormone-regulated behaviors. We propose that hormone-dependent changes in norepinephrine (NE) neurotransmission in the hypothalamus and preoptic area participate in estradiol (E2) and progesterone (P) regulation of female reproductive behavior. Preliminary work from this laboratory demonstrates that administration of physiological relevant doses of E(2) and P in vivo modulates signal transduction by two NE receptor subtypes, beta- and alpha1-adrenoceptors, in the hypothalamus and preoptic area. The goal of the proposed research is to elucidate the molecular mechanism(s) by which E2 and P modulate signal transduction by beta and alpha1-adrenoceptors in the hypothalamus and preoptic area and to relate these to the expression of lordosis behavior. The first series of experiments test the hypothesis that E2 regulates alpha1- adrenoceptor gene expression, and more specifically, expression of the alpha1B subtype. This is a significant question because NE stimulation of alpha1-adrenoceptors facilitates estrous behavior and gonadotropin release in E2-primed female rats. Using molecular techniques (Northern blots, quantitative in situ hybridization) and receptor autoradiography, the time- and dose-dependent effects of E2 and alpha1 receptor mRNA and protein will be quantified in specific hypothalamic and preoptic area nuclei and correlated with the facilitation of lordosis behavior. We will also determine whether induction of alpha1 receptors occurs in neurons that express E2 receptors. The functional activity of alpha1 receptors will be monitored by assessing coupling of alpha1A and alpha1B receptor subtypes to both the cAMP and phosphoinositol second messenger systems as a function of steroid treatment. These studies should provide insight into the molecular mechanisms underlying the rapid, synergistic effects of P on lordosis responsiveness in E2-primed animals. The second series of experiments tests the hypothesis that E2 also acts by genomic mechanisms to desensitize beta-adrenoceptor function in the hypothalamus and preoptic area. This is an important question because a critical component of E2 facilitation of reproductive behavior may be the attenuation of inhibitory actions mediated by beta receptors. The time- and dose- dependent effects of E2 on beta receptor stimulation of cAMP formation will be correlated with the facilitation of lordosis behavior. In addition, the mechanism by which E2 desensitizes beta receptor-mediated signaling will be identified.

如果一个人接受行为是神经元的产物这一观点活动，那么检查激素的影响是合理的对介导激素调节的神经回路中的脑细胞行为。我们认为去甲肾上腺素的激素依赖性变化 (NE) 下丘脑和视前区的神经传递参与女性雌二醇（E2）和孕激素（P）的调节生殖行为。该实验室的初步工作表明施用生理相关剂量 E(2)和P在体内通过两个NE受体调节信号转导下丘脑中的β-和α1-肾上腺素受体亚型视前区。拟议研究的目标是阐明 E2 和 P 调节信号转导的分子机制通过下丘脑和视前区的 β 和 α1 肾上腺素受体并将这些与脊柱前凸行为的表达联系起来。第一个一系列实验检验了 E2 调节 alpha1- 的假设肾上腺素受体基因表达，更具体地说，是 α1B 亚型。这是一个重要的问题，因为 NE 刺激 α1-肾上腺素受体促进发情行为和促性腺激素在 E2 引发的雌性大鼠中释放。使用分子技术（北印迹、定量原位杂交）和受体放射自显影，E2 和 alpha1 的时间和剂量依赖性效应受体 mRNA 和蛋白质将在特定的下丘脑中进行定量和视前区核并与促进相关脊柱前凸行为。我们还将确定是否诱导 alpha1 受体出现在表达 E2 受体的神经元中。功能性的 α1受体的活性将通过评估耦合来监测 α1A 和 α1B 受体亚型对 cAMP 和磷酸肌醇第二信使系统作为类固醇的功能治疗。这些研究应该提供对分子机制的深入了解 P 对脊柱前凸的快速协同作用的机制 E2引发的动物的反应能力。第二系列实验检验 E2 也通过基因组机制发挥作用的假设使下丘脑和视前区的β-肾上腺素受体功能脱敏区域。这是一个重要的问题，因为 E2 促进生殖行为可能是减弱由β受体介导的抑制作用。时间和剂量 E2 对 cAMP 形成的 β 受体刺激的依赖性影响将与脊柱前凸行为的促进相关。在此外，E2 使 β 受体介导的脱敏机制信令将被识别。