Neuroendocrine Bases of Reproductive Behavior

说明(申请人提供)：卵巢激素雌二醇(E2)和 孕酮(P)作用于下丘脑(HYP)和视前区(POA)，以 确保排卵前黄体生成素(黄体生成素)峰值与 生殖行为(前凸)，从而使生殖成功最大化。我们 去甲肾上腺素(NE)突触的E_2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 繁衍后代。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E_2的某些生殖活动 Hyp-POA，并与这些脑区的NE受体进行串扰。这个 拟议的研究将阐明E2和P的分子机制(S)。 HYP中IGF-1R和A1-肾上腺素能受体信号通路的相互作用 和POA，并将这些与前凸行为联系起来。《特定目标1》测试 IGF-1受体介导HYP-POA中E2作用的假说 肌醇磷脂3-激酶激活的女性生殖功能 (PI3-K)或丝裂原活化蛋白激酶(MAPK)。我们将评估(A)E2 促进前凸行为；(B)雌激素诱导的IGF-1受体密度增加 在HYPPOA；(C)E_2+P诱导的A1-肾上腺素受体与cGMP合成的偶联 在HYP-POA；和(D)E_2诱导的腹内侧棘密度增加 下丘脑神经元。特定目标2检验了E2+P依赖的假设 A1肾上腺素受体与cGMP的连接也导致MAPK的激活 HYP和POA中的信号传递。《特定目标3》测试了这样一种假设 E_2处理大鼠的Hyp-POA，P将A1-肾上腺素能受体信号转换为合成 CGMP通过升高细胞内去甲肾上腺素促进前凸的作用 钙。我们将确定A1肾上腺素受体是否通过以下方式刺激cGMP的形成 激活：(A)通过N和/或L型钙离子的细胞外钙离子内流 (B)来自内质的细胞内钙动员 (C)兰诺定敏感钙库的释放；和/或(D)生长 因子调节的激酶，如src或P13-K。具体目标4将决定 IGF-1如何显著增强HYP-POA中的A1-肾上腺素能受体信号 以及这对生殖行为是否重要。

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.