Molecular and Developmental Biological Research on Roles of a novel neuropeptide, Orexin

我们一直在通过转基因技术研究食欲素表达的神经元在调节摄食行为和觉醒中的作用。我们产生了转基因小鼠，在其中，含有食欲素的神经元通过食欲素能特异性表达截断的马查多-约瑟夫病基因产物(阿塔克辛-3)与扩展的聚谷氨酰胺拉伸来消融。这些小鼠表现出与人类发作性睡病惊人的相似之处，包括行为停止、过早进入快速眼动(REM)睡眠、睡眠模式不佳以及迟发性肥胖，尽管它们吃的东西比非转基因小鼠少。这些结果证明了含食欲素的神经元在调节警觉状态和能量稳态方面起着重要的作用。我们还证明了含食欲素的神经元能够监测外周产生的营养状态的指示物，并且是正常增强对禁食的唤醒所必需的。对表达绿色荧光蛋白的转基因小鼠分离的食欲素神经元的电生理研究表明，这些神经元的活动受到细胞外葡萄糖和瘦素脂肪的抑制，并被最近表征的胃肠肽Ghrelin刺激。增食欲素神经元可能在外周新陈代谢和中枢调节行为之间提供了一个关键的整合联系，在稀缺时期需要对自我平衡挑战做出适应性反应。

We have been studying roles of orexin-expressing neurons in the regulation of feeding behavior and wakefulness by means of transgenic technique. We generated transgenic mice in which orexin-containing neurons are ablated by orexinergic-specific expression of a truncated Machado-Joseph disease gene product (ataxin-3) with an expanded polyglutamine stretch. These mice showed a phenotype strikingly similar to human narcolepsy, including behavioral arrests, premature entry into rapid eye movement (REM) sleep, poorly consolidated sleep patterns, and a late-onset obesity, despite eating less than nontransgenic littermates. These results provide evidence that orexin-containing neurons play important roles in regulating vigilance states and energy homeostasis.We also demonstrated that orexin-containing neurons are able to monitor peripherally generated indicators of nutritional state, and are necessary for normal augmentation of arousal in response to fasting. Electrophysiological studies of isolated orexin neurons, which are specifically labeled by expression of green fluorescent protein in orexin/EGFP transgenic mice, revealed that activity of these neurons is inhibited by extracellular glucose and the adipostat leptin, and stimulated by the recently characterized gastrointestinal peptide ghrelin. Orexin neurons may provide a critical integrative link between peripheral metabolism and central regulation of behaviors required for an adaptive response to homeostatic challenges during times of scarcity.