Control of Gonadotropin Secretion during Lactation

描述（由申请方提供）：该提案的中心假设是哺乳期间GnRH/LH分泌的抑制是由于哺乳诱导的调节摄食量和能量平衡的下丘脑神经系统的改变。哺乳期的特征是由于产奶引起的过度摄食和负能量平衡。我们的研究已经确定，参与调节食物摄入/能量平衡的几种下丘脑神经肽食欲系统（NPY、食欲素、黑色素浓缩激素[MCH]、神经激肽B [NKB}）与GnRH神经元直接联系，从而提供了一个神经解剖学框架，通过该框架，指示食物摄入/能量平衡变化的信号可以直接传递到GnRH神经元。拟开展的研究将采用多学科方法探讨以下基本问题：1）促食欲和促食欲神经肽是否直接调节GnRH神经元的活性，并在哺乳期增加抑制性音调？研究将使用下丘脑外植体和电生理学来确定NPY、食欲素、MCH或NKB受体的激动剂和拮抗剂是否对GnRH神经元有直接影响。2)哺乳期特异性下丘脑背内侧核NPY的诱导是否参与GnRH活性的抑制？研究将检查哺乳特异性诱导NPY在抑制GnRH/LH中的功能作用。3)与泌乳相关的瘦素和低胰岛素血症的深度抑制是否是允许弓状核神经元驱动GnRH神经元活性和摄食过度抑制的重要许可信号？研究将使瘦素和胰岛素恢复到泌乳后水平，并确定对下丘脑神经肽摄食系统和GnRH/LH分泌恢复的影响。随后的实验将使用消融技术来确定哺乳期间GnRH神经元活性抑制中已鉴定因素的功能相关性。哺乳期大鼠提供了一种生理模型，用于研究女性的许多状况（营养不良、神经性厌食症、贪食症、运动诱发的闭经和哺乳），这些状况涉及与负能量平衡相关的生殖功能抑制。哺乳期大鼠也是慢性摄食过多的模型，并提供了机会，研究生理机制的基础条件大大增加的食物摄入量，并可能提供深入了解肥胖的原因。

DESCRIPTION (provided by applicant): The central hypothesis of this proposal is that suppression of GnRH/LH secretion during lactation is due to suckling- induced alterations in hypothalamic neural systems that regulate food intake and energy balance. Lactation is characterized by an excessive hyperphagia and negative energy balance due to milk production. Our studies have established that several hypothalamic neuropeptide orexigenic systems involved in regulating food intake/energy balance (NPY, orexin, melanin concentrating hormone [MCH], neurokinin B [NKB}) make direct connections with GnRH neurons, thus providing a neuroanatomical framework by which signals denoting changes in food intake/energy balance can be directly transmitted to GnRH neurons. The proposed studies will use a multidisciplinary approach to explore the following basic questions: 1) Do orexigenic and anorexigenic neuropeptides directly modulate GnRH neuronal activity and exert an increased inhibitory tone during lactation? Studies will use hypothalamic explants and electrophysiology to determine if agonists and antagonists to NPY, orexin, MCH or NKB receptors have direct effects on GnRH neurons. 2) Is the lactation-specific induction of NPY in the dorsomedial hypothalamic nucleus involved in the suppression of GnRH activity? Studies will examine the functional role of the suckling-specific induction of NPY in the suppression of GnRH/LH. 3) Are the profound suppression of leptin and the hypoinsulinemia associated with lactation important permissive signals that allow arcuate nucleus neurons to drive the suppression of GnRH neuronal activity and hyperphagia? Studies will restore leptin and insulin to postlactation levels and determine effects on hypothalamic neuropeptide feeding systems and on restoration of GnRH/LH secretion. Subsequent experiments will use ablation techniques to determine the functional relevance of identified factors in the suppression of GnRH neuronal activity during lactation. The lactating rat provides a physiological model for studying a number of conditions in women (undernutrition, anorexia nervosa, bulimia, exercise-induced amenorrhea and lactation) that involve a suppression of reproductive function associated with negative energy balance. The lactating rat is also a model of chronic hyperphagia and provides the opportunity to study physiological mechanisms underlying conditions of greatly increased food intake and may provide insights into causes of obesity.