Neuroendocrine Bases of Reproductive Behavior

生殖行为的神经内分泌基础

• 批准号: 6829753
• 负责人: ANNE M ETGEN
• 金额: $ 30.06万
• 依托单位: ALBERT EINSTEIN COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 1993
• 资助国家: 美国
• 起止时间: 1993-01-01 至 2006-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6829753
• 关键词: alpha adrenergic receptor; behavioral /social science research tag; biological signal transduction; calcium channel; calcium flux; cyclic GMP; enzyme activity; estradiol; female reproductive system; hormone regulation /control mechanism; hypothalamus; immunocytochemistry; insulinlike growth factor; laboratory rat; luteinizing hormone; mitogen activated protein kinase; neuroendocrine system; neurons; nitric oxide; norepinephrine; phosphatidylinositol 3 kinase; preoptic areas; progesterone; receptor expression; sex behavior; western blottings

DESCRIPTION (provided by applicant): The ovarian hormones estradiol (E2) and progesterone (P) act in the hypothalamus (HYP) and preoptic area (POA) to ensure that the preovulatory luteinizing hormone (LH) surge coincides with reproductive behavior (lordosis), thereby maximizing reproductive success. We propose that E2 and P-dependent changes in norepinephrine (NE) synaptic activity in the HYP and POA are key mediators of the neuroendocrine integration of reproduction. We propose further that insulin-like growth factor-I (IGF-1) and its receptor (IGF-1R) mediate certain reproductive actions of E2 in the HYP-POA and engage in cross talk with NE receptors in these brain areas. The proposed research will elucidate the molecular mechanism(s) by which E2 and P interact with IGF-1 R and a1-adrenergic receptor signaling pathways in the HYP and POA and will relate these to lordosis behavior. Specific Aim 1 tests the hypothesis that IGF-1 Rs mediate E2 actions in the HYP-POA that are involved in female reproductive function via activation of phosphoinositide 3-kinase (PI3-K) or mitogen-activated protein kinase (MAPK). We will assess (a) E2 facilitation of lordosis behavior; (b) E2-induced increases in IGF-1 R density in the HYPPOA; (c) E2+P-induced coupling of a1-adrenoceptors to cGMP synthesis in the HYP-POA; and (d) E2-induced increases in spine density on ventromedial hypothalamic neurons. Specific Aim 2 tests the hypothesis that E2+P-dependent linkage of a1-adrenoceptors to cGMP also results in activation of MAPK signaling in the HYP and POA. Specific Aim 3 tests the hypothesis that in the HYP-POA of E2-treated rats, P switches a1-adrenoceptor signaling to synthesis of cGMP, which mediates NE facilitation of lordosis, by elevating intracellular calcium. We will determine whether a1-adrenoceptors stimulate cGMP formation by activating: (a) extracellular calcium influx via N and/or L-type calcium channels; (b) intracellular calcium mobilization from the endoplasmic reticulum; (c) release of ryanodine-sensitive calcium stores; and/or (d) growth factor-regulated kinases such as src or P13-K. Specific Aim 4 will determine how IGF-1 acutely potentiates a1-adrenoceptor signaling in the HYP-POA of E2-treated females and whether this is important for reproductive behavior.

描述（由申请人提供）：卵巢激素雌二醇（E2）和 黄体酮 (P) 作用于下丘脑 (HYP) 和视前区 (POA) 确保排卵前黄体生成素 (LH) 激增与 生殖行为（脊柱前凸），从而最大限度地提高生殖成功率。我们 提出去甲肾上腺素 (NE) 突触中 E2 和 P 依赖性变化 HYP 和 POA 的活性是神经内分泌整合的关键介质 的繁殖。我们进一步提出胰岛素样生长因子-I (IGF-1) 及其受体 (IGF-1R) 介导 E2 的某些生殖作用 HYP-POA 并与这些大脑区域的 NE 受体进行串扰。这 拟议的研究将阐明 E2 和 P 的分子机制 与 HYP 中的 IGF-1 R 和 a1-肾上腺素受体信号通路相互作用 和 POA 并将这些与脊柱前凸行为联系起来。具体目标 1 测试 假设 IGF-1 Rs 介导 HYP-POA 中的 E2 作用，该作用参与 通过激活磷酸肌醇 3-激酶影响女性生殖功能 (PI3-K) 或丝裂原激活蛋白激酶 (MAPK)。我们将评估 (a) E2 促进脊柱前凸行为； (b) E2诱导的IGF-1 R密度增加 在 HYPPOA 中； (c) E2+P 诱导的 a1-肾上腺素受体与 cGMP 合成的偶联 在 HYP-POA 中； (d) E2 诱导腹内侧棘密度增加 下丘脑神经元。具体目标 2 检验 E2+P 依赖的假设 a1-肾上腺素受体与 cGMP 的连接也会导致 MAPK 的激活 HYP 和 POA 中的信号传导。具体目标 3 检验以下假设： E2 处理大鼠的 HYP-POA，P 将 a1-肾上腺素受体信号转导至合成 cGMP，通过升高细胞内的 NE 促进脊柱前凸 钙。我们将通过以下方式确定 a1-肾上腺素受体是否刺激 cGMP 形成 激活：(a) 通过 N 和/或 L 型钙流入细胞外钙 渠道； (b) 细胞内钙从内质动员 网状结构； (c)释放兰尼定敏感的钙储备；和/或 (d) 增长 因子调节激酶，例如 src 或 P13-K。具体目标 4 将确定 IGF-1 如何急剧增强 HYP-POA 中的 a1-肾上腺素受体信号传导 E2 治疗的雌性以及这对于生殖行为是否重要。