Immortal orexin cell transplants restore motor-arousal synchrony during cataplexy.

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  • Additional Information
    • Source:
      Publisher: Cell Press Country of Publication: England NLM ID: 9107782 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1879-0445 (Electronic) Linking ISSN: 09609822 NLM ISO Abbreviation: Curr Biol Subsets: MEDLINE
    • Publication Information:
      Publication: Cambridge, MA : Cell Press
      Original Publication: London, UK : Current Biology Ltd., c1991-
    • Subject Terms:
      Cataplexy*/therapy; Mice ; Animals ; Orexins/genetics ; Orexins/metabolism ; Proteomics ; Arousal/physiology ; Wakefulness/physiology ; Dorsal Raphe Nucleus ; Cell Transplantation
    • Abstract:
      Waking behaviors such as sitting or standing require suitable levels of muscle tone. But it is unclear how arousal and motor circuits communicate with one another so that appropriate motor tone occurs during wakefulness. Cataplexy is a peculiar condition in which muscle tone is involuntarily lost during normal periods of wakefulness. Cataplexy therefore provides a unique opportunity for identifying the signaling mechanisms that synchronize motor and arousal behaviors. Cataplexy occurs when hypothalamic orexin neurons are lost in narcolepsy; however, it is unclear if motor-arousal decoupling in cataplexy is directly or indirectly caused by orexin cell loss. Here, we used genomic, proteomic, chemogenetic, electrophysiological, and behavioral assays to determine if grafting orexin cells into the brain of cataplectic (i.e., orexin -/- ) mice restores normal motor-arousal behaviors by preventing cataplexy. First, we engineered immortalized orexin cells and found that they not only produce and release orexin but also exhibit a gene profile that mimics native orexin neurons. Second, we show that engineered orexin cells thrive and integrate into host tissue when transplanted into the brain of mice. Next, we found that grafting only 200-300 orexin cells into the dorsal raphe nucleus-a region densely innervated by native orexin neurons-reduces cataplexy. Last, we show that real-time chemogenetic activation of orexin cells restores motor-arousal synchrony by preventing cataplexy. We suggest that orexin signaling is critical for arousal-motor synchrony during wakefulness and that the dorsal raphe plays a pivotal role in coupling arousal and motor behaviors.
      Competing Interests: Declaration of interests The authors declare no competing interests.
      (Copyright © 2023 Elsevier Inc. All rights reserved.)
    • Grant Information:
      Canada CIHR
    • Contributed Indexing:
      Keywords: arousal; cataplexy; cell transplantation therapy; dorsal raphe; hypocretin; mice; narcolepsy; orexin; sleep; wakefulness
    • Accession Number:
      0 (Orexins)
    • Publication Date:
      Date Created: 20230412 Date Completed: 20230427 Latest Revision: 20230504
    • Publication Date:
      20231215
    • Accession Number:
      10.1016/j.cub.2023.03.077
    • Accession Number:
      37044089