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神经和内分泌系统的长期改变。在之前的资助期内，我们使用大鼠动物模型，证明了生殖经验改变循环催乳素和雌二醇水平、雌二醇刺激催乳素分泌、神经催乳素受体表达和催乳素受体转导机制。生殖经验对焦虑样行为的显著影响也被发现存在于有生殖经验的动物在其随后的生殖周期中，这取决于发情周期的阶段和雌性的年龄。基于这些发现，我们建议验证以下假设：“生殖经验导致雌性哺乳动物激素分泌和作用的神经调节发生根本性转变。”我们认为这种激素敏感性的转变部分是由神经和外周组织中催乳素受体功能的上调引起的，这使得内分泌靶组织对循环激素的依赖性降低。此外，我们提出雌激素受体亚型敏感性的差异变化是生殖经验的一种功能，它改变了雌性对雌激素的反应。具体研究将探讨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。另一项实验探讨了产后高泌乳素血症和生育经验年龄是否会影响生育经验对随后内分泌活动的影响。接下来，一系列的研究探讨了生殖经验对焦虑的影响，在女性生殖经验的背景下，研究了激素对焦虑的调节，以及衰老如何与生殖经验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靶组织（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改变。使用的技术包括实时RT-PCR， Western blot分析，原位杂交，放射免疫测定和行为测试。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见解，以及关于生殖经验的变革性质的重要信息。大多数雌性哺乳动物，包括女性，在她们的一生中会怀孕和生育一次或多次。迄今为止，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。目前的建议使用啮齿动物模型来研究这个问题。荷尔蒙水平，大脑对荷尔蒙的反应，以及焦虑都会随着生育经历而变化。生殖经验对乳腺和肝脏激素受体的影响也将与大脑中的激素受体进行比较，以确定已建立的生殖经验引起的变化的呼吸。总体而言，生殖经历引起的内分泌活动变化可能影响成年后的内分泌相关疾病和行为，即乳腺癌、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.