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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >Orexin receptor 2 expression in the posterior hypothalamus rescues sleepiness in narcoleptic mice
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Orexin receptor 2 expression in the posterior hypothalamus rescues sleepiness in narcoleptic mice

机译：下丘脑后部的Orexin受体2表达可挽救麻醉性发作小鼠的困倦

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摘要

Narcolepsy is caused by a loss of orexin/hypocretin signaling, resulting in chronic sleepiness, fragmented non-rapid eye movement sleep, and cataplexy. To identify the neuronal circuits underlying narcolepsy, we produced a mouse model in which a loxP-flanked gene cassette disrupts production of the orexin receptor type 2 (OX2R; also known as HCRTR2), but normal OX2R expression can be restored by Cre recombinase. Mice lacking OX2R signaling had poor maintenance of wakefulness indicative of sleepiness and fragmented sleep and lacked any electrophysiological response to orexin-A in the wake-prompting neurons of the tuberomammillary nucleus. These defects were completely recovered by crossing them with mice that express Cre in the female germline, thus globally deleting the transcription-disrupter cassette. Then, by using an adeno-associated viral vector coding for Cre recombinase, we found that focal restoration of OX2R in neurons of the tuberomammillary nucleus and adjacent parts of the posterior hypothalamus completely rescued the sleepiness of these mice, but their fragmented sleep was unimproved. These observations demonstrate that the tuberomammillary region plays an essential role in the wake-promoting effects of orexins, but orexins must stabilize sleep through other targets.
机译：发作性睡病是由食欲素/促胰泌素信号转导的缺失引起的，从而导致长期嗜睡，不快速的眼动睡眠不足和瘫痪。为了鉴定发作性睡病的神经回路，我们建立了一个小鼠模型，其中loxP侧翼的基因盒破坏了2型食欲肽受体的产生（OX2R；也称为HCRTR2），但是可以通过Cre重组酶恢复正常的OX2R表达。缺少OX2R信号的小鼠的清醒性维持较差，表明嗜睡和睡眠分散，并且在提示结核母乳头核的神经元中对orexin-A缺乏任何电生理反应。通过将这些缺陷与在雌性种系中表达Cre的小鼠杂交，可以完全恢复这些缺陷，从而全面删除转录干扰盒。然后，通过使用编码Cre重组酶的腺相关病毒载体，我们发现结核母乳核和下丘脑后部相邻部分神经元中OX2R的局灶性恢复完全挽救了这些小鼠的嗜睡性，但其零碎的睡眠并未得到改善。这些观察表明，结核母乳突区域在食欲素的唤醒促进作用中起着重要作用，但是食欲素必须通过其他靶点来稳定睡眠。

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    Takatoshi Mochizuki; Elda Arrigoni; Jacob N. Marcus; Erika L. Clark; Mihoko Yamamoto; Michael Honer; Edilio Borroni; Bradford B. Lowell; Joel K. Elmquist; Thomas E. Scammell;

  • 作者单位

    Department of Neurology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215;

    Department of Neurology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215;

    Division of Endocrinology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215 Merck Research Laboratories, West Point, PA 19486;

    Department of Neurology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215;

    Department of Neurology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215;

    F. Hoffmann-La Roche, CH-4070 Basel, Switzerland;

    F. Hoffmann-La Roche, CH-4070 Basel, Switzerland;

    Division of Endocrinology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215;

    Division of Endocrinology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215 Departments of Internal Medicine and Pharmacology, Division of Hypothalamic Research, University of Texas Southwestern Medical Center, Dallas, TX 75390;

    Department of Neurology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215;

  • 收录信息 美国《科学引文索引》(SCI);美国《生物学医学文摘》(MEDLINE);美国《化学文摘》(CA);
  • 原文格式 PDF
  • 正文语种 eng
  • 中图分类
  • 关键词

    histamine; Cre-loxP; G protein-coupled receptors; arousal;

    机译：组胺;Cre-loxP;G蛋白偶联受体;唤起;

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