Development of Leptin-Sensitive Hypothalamic Pathways

描述（由申请人提供）：本研究的长期目标是了解脂肪细胞来源的激素瘦素如何作用于下丘脑神经元，以调节参与哺乳动物体内平衡调节的中枢神经通路的发育。这一目标的核心是确定瘦素如何影响从下丘脑弓状核（ARM）到室旁核（PVH）的神经投射的发展，PVH是整合与周围能量储存和神经内分泌需求相关的信息的关键部位。在过去的项目期间，我们证明了瘦素是ARM投影正常发育所必需的，但出生后瘦素的长期功能后果仍有待确定，关键时期尚未明确定义。在这个建议中提出的总体假设是，在一个离散的产后关键时期暴露于瘦素足以永久地组织来自弓形核的投射。下丘脑调节食物摄入和能量代谢的关键方面，并且在这一发育关键时期新生儿营养的改变通过伴随的循环瘦素水平的变化影响生长。我们将通过使用小鼠模型来验证这一假设，以解决以下具体目标。首先，我们将评估出生后瘦素暴露对成年ob/ob小鼠功能拯救缺陷的能力（Specific Aim 1）。其次，我们将利用神经解剖学技术来评估出生后瘦素暴露对成年ob/ob小鼠PVH神经元识别神经输入的影响（Specific Aim 2）。第三，我们将利用前两个特定目标中开发的生理和神经解剖学分析来确定瘦素对ARM中NPY/AgRP和POMC神经元投射的发育作用的关键时期，并确定相关的长期生理后果（特定目标3）。最后，我们将研究营养改变对出生后瘦素激增的影响，并确定外源性出生后瘦素是否会影响在出生后营养过剩和营养不足的环境中观察到的小鼠的追赶生长模式（Specific Aim 4）。这项研究的结果将有助于我们对瘦素作为下丘脑关键发育因子的认识，并可能为新生儿营养环境如何对大脑结构和生命中能量平衡的调节施加持久影响提供线索。

DESCRIPTION (provided by applicant): The long-range goal of this research is to understand how the adipocyte-derived hormone leptin acts on hypothalamic neurons to regulate development of central neural pathways involved in the regulation of mammalian homeostasis. Central to this goal is determining how leptin influences development of neural projections from the arcuate nucleus of the hypothalamus (ARM) to the paraventricular nucleus (PVH), key sites for integration of information related to peripheral energy stores and neuroendocrine demands. During the past project period we demonstrated that leptin is required for normal development of ARM projections, yet the long-term functional consequences of postnatal leptin remain to be established, and the critical period is not clearly defined. The overall hypothesis addressed in this proposal is that exposure to leptin during a discrete postnatal critical period is sufficient to permanently organize projections from the arcuate nucleus of.the hypothalamus that regulate food intake and key aspects of energy metabolism, and that alterations in neonatal nutrition during this developmental critical period influence growth through accompanying changes in levels of circulating leptin. We will test this hypothesis by using mouse models to address the following specific aims. First, we will evaluate the ability of postnatal leptin exposure to functionally rescue deficits in adult ob/ob mice (Specific Aim 1). Second, we will utilize neuroanatomical techniques to assess the impact of postnatal leptin exposure on identified neural inputs to PVH neurons in adult ob/ob mice (Specific Aim 2). Third, we will utilize the physiological and neuroanatomical assays developed during the first 2 specific aims to define the critical period for the developmental actions of leptin on projections of NPY/AgRP and POMC neurons in the ARM, and to identify associated long term physiological consequences (Specific Aim 3). Finally, we will study the impact of altered nutrition on the postnatal leptin surge and determine whether exogenous postnatal leptin can influence the pattern of catch up growth observed in mice derived from over- and under-nutritional postnatal environments (Specific Aim 4). The results of the proposed research will contribute significantly to our emerging appreciation of leptin as a key developmental factor in the hypothalamus, and may provide clues about how the neonatal nutritional environment imposes enduring consequences on brain architecture and the regulation of energy balance throughout life.