Metabolic Regulation of Reproduction

描述(由申请人提供)： 这项建议的总体目标是更多地了解甘丙肽样肽(GALP)神经元的生理学，特别是在糖尿病的背景下。主要目的是1)确定GALP神经元相对于其他已知的生殖和摄食神经内分泌介质的解剖组织，并了解这一回路在糖尿病状态下是否发生改变；2)通过检测集中式注射GALP对I型糖尿病啮齿动物模型生殖轴和行为的影响，探讨GALP在介导瘦素和胰岛素对生殖系统影响中的作用。所有的实验操作都将在糖尿病雄性大鼠身上进行，并与正常对照组进行比较。在不改变糖皮质激素水平的情况下，皮下注射链脲佐菌素可在至少95%的动物中诱发糖尿病，从而在药理学上诱导糖尿病状态。对照动物将被注射车辆。为了实现这些目标，将使用各种神经解剖学技术，包括逆行追踪结合单标记和双标记免疫细胞化学，来绘制连接GALP和下丘脑中其他神经递质系统的下丘脑回路。对脑内注射GALP和/或甘丙素后男性特异性性行为的分析将为这些神经肽在生殖行为调节中的作用提供证据。进一步的温度定量杂交将被用来确定荷尔蒙和行为操作对下丘脑GALP mRNA的影响。希望这些基本知识将有助于更好地了解与糖尿病有关的生殖障碍，从而为治疗糖尿病提供一条开明的道路。

DESCRIPTION (provided by applicant): The overall goal of this proposal is to understand more about the physiology of galanin-like peptide (GALP) neurons, and particularly within the context of diabetes. The primary aims are 1) to determine the anatomical organization of GALP neurons with respect to other known neuroendocrine mediators of reproduciton and feeding and to learn wether this circuitry is altered in the diabetic state; and 2) to explore the role of GALP in mediating the effects of leptin and insulin on the reproductive system, by examining the effects of centrally administered GALP on the reproductive axis and behaviors in a rodent model of type I diabetes. All experimental manipulations will be carried out in the diabetic male rat and compared to normal controls. Diabetic status will induced pharmacologically with subcutaneous injections of streptozotocin at a dose known to induce diabetes in at least 95% of animals without altering glucocorticoid levels. Control animals will be injected withvehicle. To accomplish these goals, the use of various neuroanatomical techniques, including retrograde tract-tracing combined with single- and double-label immunocytochemistry, will be used to map the hypothalamic circuitry linking GALP to other neurotransmitter systems in the hypothalamus. Analysis of male-specific sex behaivors following intracerebral injections of GALP and/or galanin will provide evidence for the role of these neuropeptides in the regulation of reproductive behaivors. Furthermorequantitative in sity hybridization will be used to determine the effects of hormonal and behavioral manipulations on GALP mRNA within the hypothalamus. It is hoped that this basic knowledge will lead to a better understanding of disorders of reproduction that are associated with diabetes and thus provide an enlightened path towards their treatment.