A genetic approach for investigating vagal sensory roles in regulation of gastrointestinal function and food intake
A genetic approach for investigating vagal sensory roles in regulation of gastrointestinal function and food intake
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DOI：
10.1016/j.autneu.2006.03.005
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发表时间：
2006-06-30
影响因子：
2.7
通讯作者：
Fox, Edward Alan
中科院分区：
文献类型：
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作者：
Fox, Edward Alan
迷走神经对胃肠道的感觉神经支配在胃肠道功能和进食行为的调节中发挥着重要作用。这种神经支配由大量的感觉通路组成，每一个都来自不同的感觉受体群体。这些通路与迷走神经传出、交感神经和肠道系统的密切联系阻碍了对这些通路功能的理解，这使得难以选择性地标记或操纵它们。我们认为，遗传学的方法可以克服这些障碍。为了说明这一战略的潜在价值，以及深入了解其应用，研究中枢神经系统的途径和外周组织参与的能量平衡，受益于使用基因操作进行审查。接下来，我们的研究审查的可行性，使用突变的发育基因操纵个人迷走神经传入通路。这些实验的特点机械感受器的形态，密度和分布，以及喂养模式在四个可行的突变小鼠品系。在每个菌株中，一个单一的人口迷走神经机械感受器支配胃肠道的肌肉壁被改变，并与选择性影响喂养模式，从而支持这种策略的可行性。然而，必须解决这一方法的两个局限性，使其充分发挥潜力。首先，胃肠道外组织的突变效应可能导致胃肠道功能或进食的变化。此外，发育基因的敲除通常是致命的，阻止了对成熟神经支配和摄食行为的分析。为了解决这些问题，我们建议开发限制于特定胃肠道组织的条件基因敲除。两个感兴趣的基因是脑源性神经营养因子（BDNF）和神经营养素-3（NT-3），它们对迷走神经传入发育至关重要。创建这些基因的条件性敲除需要了解它们在发育过程中的胃肠道表达，而这方面知之甚少。初步研究显示，在发育过程中，BDNF和NT-3分别在几个胃肠道区域表达，并且它们的表达模式在某些组织中重叠，但在其他组织中不同。重要的是，表达BDNF或NT-3的GI组织受迷走神经传入神经支配，这些神经营养因子的表达发生在轴突侵入和受体形成期间，与BDNF或NT-3在这些过程和受体存活中的作用一致。这些结果提供了将BDNF或NT-3敲除靶向特定胃肠道组织的基础，并可能改变仅在该组织中的迷走传入神经支配（例如，平滑肌对粘膜）。成功地选择性改变迷走神经GI传入通路的条件性BDNF或NT-3敲除对于理解该通路在GI功能和食物摄入中的作用将是有价值的。(c)2006 Elsevier B. V.保留所有权利。
Sensory innervation of the gastrointestinal (GI) tract by the vagus nerve plays important roles in regulation of GI function and feeding behavior. This innervation is composed of a large number of sensory pathways, each arising from a different population of sensory receptors. Progress in understanding the functions of these pathways has been impeded by their close association with vagal efferent, sympathetic, and enteric systems, which makes it difficult to selectively label or manipulate them. We suggest that a genetic approach may overcome these barriers. To illustrate the potential value of this strategy, as well as to gain insights into its application, investigations of CNS pathways and peripheral tissues involved in energy balance that benefited from the use of gene manipulations are reviewed. Next, our studies examining the feasibility of using mutations of developmental genes for manipulating individual vagal afferent pathways are reviewed. These experiments characterized mechanoreceptor morphology, density and distribution, and feeding patterns in four viable mutant mouse strains. In each strain a single population of vagal mechanoreceptors innervating the muscle wall of the GI tract was altered, and was associated with selective effects on feeding patterns, thus supporting the feasibility of this strategy. However, two limitations of this approach must be addressed for it to achieve its full potential. First, mutation effects in tissues outside the GI tract can contribute to changes in GI function or feeding. Additionally, knockouts of developmental genes are often lethal, preventing analysis of mature innervation and ingestive behavior. To address these issues, we propose to develop conditional gene knockouts restricted to specific GI tract tissues. Two genes of interest are brain-derived neurotrophic factor (BDNF) and neurotrophin-3 (NT-3), which are essential for vagal afferent development. Creating conditional knockouts of these genes requires knowledge of their GI tract expression during development, which little is known about. Preliminary investigation revealed that during development BDNF and NT-3 are each expressed in several GI tract regions, and that their expression patterns overlap in some tissues, but are distinct in others. Importantly, GI tissues that express BDNF or NT-3 are innervated by vagal afferents, and expression of these neurotrophins occurs during the periods of axon invasion and receptor formation, consistent with roles for BDNF or NT-3 in these processes and in receptor survival. These results provide a basis for targeting BDNF or NT-3 knockouts to specific GI tract tissues, and potentially altering vagal afferent innervation only in that tissue (e.g., smooth muscle vs. mucosa). Conditional BDNF or NT-3 knockouts that are successful in selectively altering a vagal GI afferent pathway will be valuable for developing an understanding of that pathway's roles in GI function and food intake. (c) 2006 Elsevier B.V. All rights reserved.