Neural and Endocrine Consequences of Parity

描述(由申请人提供)：生殖经历(即怀孕、分娩和哺乳)会导致雌性哺乳动物的神经和内分泌系统发生长期变化。在之前的资助期间，我们使用一个大鼠动物模型，证明了生殖经历改变了循环中的催乳素和雌二醇水平，雌二醇刺激的催乳素分泌，神经性催乳素受体的表达，以及催乳素受体的转导机制。在随后的生殖周期中，生殖经历对焦虑样行为的显著影响也被发现，这取决于发情周期的阶段和雌性的年龄。基于这些发现，我们建议检验以下假设：“生殖经历导致雌性哺乳动物荷尔蒙分泌和行为的神经调节发生根本性变化。”我们认为，这种激素敏感性的变化部分是由于神经和外周组织中催乳素受体功能的上调，使内分泌靶组织对循环激素的依赖减少。此外，我们认为雌激素受体亚型敏感性的不同变化是生殖经验的函数，从而改变了女性对雌激素的反应。具体研究将调查生殖经验对催乳素和雌二醇受体表达的影响，催乳素转导机制，以及雌二醇和催乳素受体敏感性的变化。另一项实验考察了产后高催乳素血症和生育经历的年龄是否有助于生育经历对随后的内分泌活动的影响。接下来，一系列研究调查了生育经历对焦虑的影响，考察了在女性生育经历的背景下，焦虑的激素调节，以及年龄可能如何与生育经历相互作用来影响焦虑。最后，研究了生殖经验对非神经内分泌目标组织(即乳腺组织和肝脏)的可能影响，以确定非神经组织中的激素受体系统是否像在大脑中一样发生了变化。使用的技术包括实时RT-PCR、Western印迹分析、原位杂交、放射免疫分析和行为测试。这些研究的结果应该提供关于下丘脑在神经内分泌可塑性中的作用的洞察力，以及关于生殖体验的变革性的重要信息。大多数雌性哺乳动物，包括女性，在一生中怀孕并分娩一次或多次。到目前为止，很少有人注意到这种生殖经历对成年后女性生理和健康的长期影响。本提案使用啮齿动物模型来研究这一问题。荷尔蒙水平、大脑对荷尔蒙的反应性和焦虑将在生育经历后表现出来。生育经验对乳腺和肝脏激素受体的影响也将与大脑中的作用进行比较，以确定既定生育经验引起的变化。总体而言，生殖经验引起的内分泌活动变化可能会影响成年后与内分泌相关的疾病和行为，如乳腺癌、自身免疫性疾病和产后情绪障碍。

DESCRIPTION (provided by applicant): Reproductive experience (i.e. pregnancy, parturition and lactation) results in long lasting alterations in the female mammal's neural and endocrine systems. In the previous grant period, using a rat animal model, we demonstrated that reproductive experience alters circulating prolactin and estradiol levels, estradiol-stimulated prolactin secretion, neural prolactin receptor expression, and prolactin receptor transduction mechanisms. Significant effects of reproductive experience on anxiety-like behavior were also found in reproductively experienced animals during their subsequent reproductive cycles that were dependent upon the stage of the estrous cycle and the age of the female. Based on these findings, we propose to test the following hypothesis: "Reproductive Experience Induces a Fundamental Shift in the Neural Regulation of Hormone Secretion and Action in Female Mammals." We propose that this shift in hormone sensitivity is brought about in part by an up-regulation of prolactin receptor function in both neural and peripheral tissues that renders endocrine target tissues less dependent on circulating hormones. In addition, we propose that differential shifts in the sensitivities of estrogen receptor subtypes develop as a function of reproductive experience that alter the female's responses to estrogen. Specific studies will investigate the effects of reproductive experience on prolactin and estradiol receptor expression, prolactin transduction mechanisms, and shifts in estradiol and prolactin receptor sensitivity. Another experiment examines whether postpartum hyperprolactinemia and the age of reproductive experience contribute to the effects of reproductive experience on subsequent endocrine activity. Next, a series of studies investigate the impact of reproductive experience on anxiety, examining the hormonal regulation of anxiety within the context of the female's reproductive experience and how aging may interact with reproductive experience to affect anxiety. Finally, the possible effects of reproductive experience on non-neural endocrine target tissues, i.e. mammary tissue and liver, are examined to determine whether hormone receptor systems are altered in non-neural tissues as they are in the brain. Techniques used include real time RT-PCR, Western blot analysis, in situ hybridization, radioimmunoassay, and behavioral testing. The results of these studies should provide insight regarding the role of the hypothalamus in neuroendocrine plasticity and significant information regarding the transformative nature of reproductive experience. Most female mammals, including women, become pregnant and give birth one or more times over the course of their lifetimes. To date, little attention has been given to the long-term impact of this reproductive experience on the female's physiology and health later in adulthood. The present proposal uses a rodent model to examine this issue. Hormone levels, the responsiveness of the brain to hormones, and anxiety will be characterized following reproductive experience. The effects of reproductive experience on mammary gland and liver hormone receptors will also be compared with those in brain to determine the breath of established reproductive experience-induced changes. Overall, reproductive experience-induced shifts in endocrine activities may affect endocrine-related diseases and behaviors later in adulthood, i.e. breast cancer, autoimmune diseases, and postpartum mood disorders.