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Dissociating orexin-dependent and -independent functions of orexin neurons using novel Orexin-Flp knock-in mice

Uninterrupted arousal is important for survival during threatening situations. Activation of orexin/hypocretin neurons is implicated in sustained arousal. However, orexin neurons produce and release orexin as well as several co-transmitters including dynorphin and glutamate. To disambiguate orexin-d...

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Autores principales: Chowdhury, Srikanta, Hung, Chi Jung, Izawa, Shuntaro, Inutsuka, Ayumu, Kawamura, Meiko, Kawashima, Takashi, Bito, Haruhiko, Imayoshi, Itaru, Abe, Manabu, Sakimura, Kenji, Yamanaka, Akihiro
Formato: Online Artículo Texto
Lenguaje:English
Publicado: eLife Sciences Publications, Ltd 2019
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6548533/
https://www.ncbi.nlm.nih.gov/pubmed/31159922
http://dx.doi.org/10.7554/eLife.44927
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author Chowdhury, Srikanta
Hung, Chi Jung
Izawa, Shuntaro
Inutsuka, Ayumu
Kawamura, Meiko
Kawashima, Takashi
Bito, Haruhiko
Imayoshi, Itaru
Abe, Manabu
Sakimura, Kenji
Yamanaka, Akihiro
author_facet Chowdhury, Srikanta
Hung, Chi Jung
Izawa, Shuntaro
Inutsuka, Ayumu
Kawamura, Meiko
Kawashima, Takashi
Bito, Haruhiko
Imayoshi, Itaru
Abe, Manabu
Sakimura, Kenji
Yamanaka, Akihiro
author_sort Chowdhury, Srikanta
collection PubMed
description Uninterrupted arousal is important for survival during threatening situations. Activation of orexin/hypocretin neurons is implicated in sustained arousal. However, orexin neurons produce and release orexin as well as several co-transmitters including dynorphin and glutamate. To disambiguate orexin-dependent and -independent physiological functions of orexin neurons, we generated a novel Orexin-flippase (Flp) knock-in mouse line. Crossing with Flp-reporter or Cre-expressing mice showed gene expression exclusively in orexin neurons. Histological studies confirmed that orexin was knock-out in homozygous mice. Orexin neurons without orexin showed altered electrophysiological properties, as well as received decreased glutamatergic inputs. Selective chemogenetic activation revealed that both orexin and co-transmitters functioned to increase wakefulness, however, orexin was indispensable to promote sustained arousal. Surprisingly, such activation increased the total time spent in cataplexy. Taken together, orexin is essential to maintain basic membrane properties and input-output computation of orexin neurons, as well as to exert awake-sustaining aptitude of orexin neurons.
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spelling pubmed-65485332019-06-12 Dissociating orexin-dependent and -independent functions of orexin neurons using novel Orexin-Flp knock-in mice Chowdhury, Srikanta Hung, Chi Jung Izawa, Shuntaro Inutsuka, Ayumu Kawamura, Meiko Kawashima, Takashi Bito, Haruhiko Imayoshi, Itaru Abe, Manabu Sakimura, Kenji Yamanaka, Akihiro eLife Neuroscience Uninterrupted arousal is important for survival during threatening situations. Activation of orexin/hypocretin neurons is implicated in sustained arousal. However, orexin neurons produce and release orexin as well as several co-transmitters including dynorphin and glutamate. To disambiguate orexin-dependent and -independent physiological functions of orexin neurons, we generated a novel Orexin-flippase (Flp) knock-in mouse line. Crossing with Flp-reporter or Cre-expressing mice showed gene expression exclusively in orexin neurons. Histological studies confirmed that orexin was knock-out in homozygous mice. Orexin neurons without orexin showed altered electrophysiological properties, as well as received decreased glutamatergic inputs. Selective chemogenetic activation revealed that both orexin and co-transmitters functioned to increase wakefulness, however, orexin was indispensable to promote sustained arousal. Surprisingly, such activation increased the total time spent in cataplexy. Taken together, orexin is essential to maintain basic membrane properties and input-output computation of orexin neurons, as well as to exert awake-sustaining aptitude of orexin neurons. eLife Sciences Publications, Ltd 2019-06-04 /pmc/articles/PMC6548533/ /pubmed/31159922 http://dx.doi.org/10.7554/eLife.44927 Text en © 2019, Chowdhury et al http://creativecommons.org/licenses/by/4.0/ http://creativecommons.org/licenses/by/4.0/This article is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use and redistribution provided that the original author and source are credited.
spellingShingle Neuroscience
Chowdhury, Srikanta
Hung, Chi Jung
Izawa, Shuntaro
Inutsuka, Ayumu
Kawamura, Meiko
Kawashima, Takashi
Bito, Haruhiko
Imayoshi, Itaru
Abe, Manabu
Sakimura, Kenji
Yamanaka, Akihiro
Dissociating orexin-dependent and -independent functions of orexin neurons using novel Orexin-Flp knock-in mice
title Dissociating orexin-dependent and -independent functions of orexin neurons using novel Orexin-Flp knock-in mice
title_full Dissociating orexin-dependent and -independent functions of orexin neurons using novel Orexin-Flp knock-in mice
title_fullStr Dissociating orexin-dependent and -independent functions of orexin neurons using novel Orexin-Flp knock-in mice
title_full_unstemmed Dissociating orexin-dependent and -independent functions of orexin neurons using novel Orexin-Flp knock-in mice
title_short Dissociating orexin-dependent and -independent functions of orexin neurons using novel Orexin-Flp knock-in mice
title_sort dissociating orexin-dependent and -independent functions of orexin neurons using novel orexin-flp knock-in mice
topic Neuroscience
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6548533/
https://www.ncbi.nlm.nih.gov/pubmed/31159922
http://dx.doi.org/10.7554/eLife.44927
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