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Published on: June 19, 2019
Conditional ablation of orexin/hypocretin neurons: a new mouse model for the study of narcolepsy and orexin system
Sawako Tabuchi1, Tomomi Tsunematsu, Sarah W Black
1Research Institute of Environmental Medicine, Nagoya University, Nagoya, 464-8601, Japan, Department of Physiological Sciences, The Graduate University for Advanced Studies, Okazaki 444-8585, Japan, Japan Society for the Promotion of Science, Tokyo 102-8472, Japan, Center for Neuroscience, Biosciences Division, SRI International, Menlo Park, California 94025, Division of Cell Signaling, National Institute for Physiological Sciences, National Institute of Natural Sciences, Okazaki 444-8787, Japan, Center for Multidisciplinary Brain Research, National Institute for Physiological Sciences, National Institute of Natural Sciences, Okazaki 444-8585, Japan, Division of Endocrinology and Metabolism, National Institute for Physiological Sciences, National Institute of Natural Sciences, Okazaki 444-8585, Japan, and Department of Molecular Neuroscience and Integrative Physiology, Faculty of Medicine, Kanazawa University, Kanazawa, Ishikawa 920-8640, Japan.
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.
Insights
A new mouse model mimics human narcolepsy by targeting orexin/hypocretin neurons postpubertally. This model shows rapid cell loss, cataplexy, and metabolic changes, offering insights into narcolepsy and related functions.
Area of Science:
- Neuroscience
- Sleep Medicine
- Genetics
Background:
- Narcolepsy is a sleep disorder caused by the loss of orexin/hypocretin neurons in the hypothalamus.
- Existing mouse models of narcolepsy typically involve early-onset genetic defects, not reflecting the postpubertal onset common in humans.
Purpose of the Study:
- To develop a novel mouse model that more accurately replicates the postpubertal onset and progression of human narcolepsy.
- To investigate the effects of targeted orexin neuron loss on sleep architecture, cataplexy, and metabolic functions.
Main Methods:
- Utilized a Tet-off system to control the expression of diphtheria toxin A (DTA) in orexin neurons.
- Administered doxycycline to regulate DTA expression and induce targeted neurodegeneration in adult mice.
- Monitored sleep patterns, observed for cataplexy, and measured body weight and food consumption.
Main Results:
- Doxycycline removal led to rapid (80% within 7 days) loss of orexin neurons in adult mice.
- Disrupted sleep architecture and the development of cataplexy were observed.
- Induced weight gain without altered food intake, mirroring metabolic disturbances in human narcolepsy.
Conclusions:
- The developed Tet-off DTA mouse model provides a faithful representation of postpubertal narcolepsy onset and progression.
- This model is valuable for studying the pathophysiology of narcolepsy, including cataplexy and metabolic dysregulation.
- It serves as a platform for pharmacological interventions and research into network reorganization following orexin system loss.
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