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Articles, Neurobiology of Disease

Conditional Ablation of Orexin/Hypocretin Neurons: A New Mouse Model for the Study of Narcolepsy and Orexin System Function

Sawako Tabuchi, Tomomi Tsunematsu, Sarah W. Black, Makoto Tominaga, Megumi Maruyama, Kazuyo Takagi, Yasuhiko Minokoshi, Takeshi Sakurai, Thomas S. Kilduff and Akihiro Yamanaka
Journal of Neuroscience 7 May 2014, 34 (19) 6495-6509; DOI: https://doi.org/10.1523/JNEUROSCI.0073-14.2014
Sawako Tabuchi
1Research Institute of Environmental Medicine, Nagoya University, Nagoya, 464-8601, Japan,
2Department of Physiological Sciences, The Graduate University for Advanced Studies, Okazaki 444-8585, Japan,
3Japan Society for the Promotion of Science, Tokyo 102-8472, Japan,
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Tomomi Tsunematsu
1Research Institute of Environmental Medicine, Nagoya University, Nagoya, 464-8601, Japan,
3Japan Society for the Promotion of Science, Tokyo 102-8472, Japan,
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Sarah W. Black
4Center for Neuroscience, Biosciences Division, SRI International, Menlo Park, California 94025,
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Makoto Tominaga
2Department of Physiological Sciences, The Graduate University for Advanced Studies, Okazaki 444-8585, Japan,
5Division of Cell Signaling, National Institute for Physiological Sciences, National Institute of Natural Sciences, Okazaki 444-8787, Japan,
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Megumi Maruyama
1Research Institute of Environmental Medicine, Nagoya University, Nagoya, 464-8601, Japan,
6Center for Multidisciplinary Brain Research, National Institute for Physiological Sciences, National Institute of Natural Sciences, Okazaki 444-8585, Japan,
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Kazuyo Takagi
2Department of Physiological Sciences, The Graduate University for Advanced Studies, Okazaki 444-8585, Japan,
7Division of Endocrinology and Metabolism, National Institute for Physiological Sciences, National Institute of Natural Sciences, Okazaki 444-8585, Japan, and
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Yasuhiko Minokoshi
2Department of Physiological Sciences, The Graduate University for Advanced Studies, Okazaki 444-8585, Japan,
7Division of Endocrinology and Metabolism, National Institute for Physiological Sciences, National Institute of Natural Sciences, Okazaki 444-8585, Japan, and
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Takeshi Sakurai
8Department of Molecular Neuroscience and Integrative Physiology, Faculty of Medicine, Kanazawa University, Kanazawa, Ishikawa 920-8640, Japan
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Thomas S. Kilduff
4Center for Neuroscience, Biosciences Division, SRI International, Menlo Park, California 94025,
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Akihiro Yamanaka
1Research Institute of Environmental Medicine, Nagoya University, Nagoya, 464-8601, Japan,
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Abstract

The sleep disorder narcolepsy results from loss of hypothalamic orexin/hypocretin neurons. Although narcolepsy onset is usually postpubertal, current mouse models involve loss of either orexin peptides or orexin neurons from birth. To create a model of orexin/hypocretin deficiency with closer fidelity to human narcolepsy, diphtheria toxin A (DTA) was expressed in orexin neurons under control of the Tet-off system. Upon doxycycline removal from the diet of postpubertal orexin-tTA;TetO DTA mice, orexin neurodegeneration was rapid, with 80% cell loss within 7 d, and resulted in disrupted sleep architecture. Cataplexy, the pathognomic symptom of narcolepsy, occurred by 14 d when ∼5% of the orexin neurons remained. Cataplexy frequency increased for at least 11 weeks after doxycycline. Temporary doxycycline removal followed by reintroduction after several days enabled partial lesion of orexin neurons. DTA-induced orexin neurodegeneration caused a body weight increase without a change in food consumption, mimicking metabolic aspects of human narcolepsy. Because the orexin/hypocretin system has been implicated in the control of metabolism and addiction as well as sleep/wake regulation, orexin-tTA; TetO DTA mice are a novel model in which to study these functions, for pharmacological studies of cataplexy, and to study network reorganization as orexin input is lost.

  • diphtheria toxin A fragment
  • hypocretin
  • model mice
  • narcolepsy
  • orexin
  • transgenic

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The Journal of Neuroscience: 34 (19)
Journal of Neuroscience
Vol. 34, Issue 19
7 May 2014
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Conditional Ablation of Orexin/Hypocretin Neurons: A New Mouse Model for the Study of Narcolepsy and Orexin System Function
Sawako Tabuchi, Tomomi Tsunematsu, Sarah W. Black, Makoto Tominaga, Megumi Maruyama, Kazuyo Takagi, Yasuhiko Minokoshi, Takeshi Sakurai, Thomas S. Kilduff, Akihiro Yamanaka
Journal of Neuroscience 7 May 2014, 34 (19) 6495-6509; DOI: 10.1523/JNEUROSCI.0073-14.2014

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Conditional Ablation of Orexin/Hypocretin Neurons: A New Mouse Model for the Study of Narcolepsy and Orexin System Function
Sawako Tabuchi, Tomomi Tsunematsu, Sarah W. Black, Makoto Tominaga, Megumi Maruyama, Kazuyo Takagi, Yasuhiko Minokoshi, Takeshi Sakurai, Thomas S. Kilduff, Akihiro Yamanaka
Journal of Neuroscience 7 May 2014, 34 (19) 6495-6509; DOI: 10.1523/JNEUROSCI.0073-14.2014
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Keywords

  • diphtheria toxin A fragment
  • hypocretin
  • model mice
  • narcolepsy
  • orexin
  • transgenic

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