Neuroendocrine Bases of Reproductive Behavior

性状（由申请人提供）：卵巢激素雌二醇（E2）和 孕酮（P）作用于下丘脑（HYP）和视前区（POA）， 确保排卵前促黄体生成激素（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）突触中的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 繁殖的过程。我们进一步提出，胰岛素样生长因子-I（IGF-1） 及其受体（IGF-1 R）介导E2在生殖细胞中的某些生殖作用。 HYP-POA并与这些大脑区域中的NE受体进行串扰。的 拟议的研究将阐明E2和P 与HYP中IGF-1 R和α 1-肾上腺素能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 R介导HYP-POA中E2作用，参与 通过激活磷酸肌醇3-激酶实现女性生殖功能 （PI 3-K）或丝裂原活化蛋白激酶（MAPK）。我们将评估（a）E2 （B）E2诱导的IGF-1 R密度增加 （c）E2+ P诱导的α 1-肾上腺素受体与cGMP合成的偶联 HYP-POA;（d）E2诱导的腹内侧棘密度增加 下丘脑神经元具体目标2检验了E2+ P依赖性 α 1-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。具体目标3检验了以下假设： 在E2处理的大鼠的HYP-POA中，P将α 1-肾上腺素受体信号转换为合成 cGMP，其通过升高细胞内 钙我们将确定是否α 1肾上腺素受体刺激cGMP的形成， 激活：（a）通过N和/或L-型钙离子通道的细胞外钙内流 通道;（B）从内质网的细胞内钙动员 网;（c）释放ryanodine敏感的钙储存;和/或（d）生长 因子调节激酶如src或P13-K。具体目标4将决定 IGF-1如何急性增强α 1-肾上腺素能受体信号在HYP-POA的 E2处理的女性，这是否是重要的生殖行为。

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.