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Narcolepsy and the hypocretin system—where motion meets emotion

Nature Clinical Practice Neurology volume 2, pages 548–556 (2006)Cite this article

Abstract

Narcolepsy is a neurological disorder that is characterized by excessive daytime sleepiness and cataplexy—a loss of muscle tone generally triggered by certain strong emotions with sudden onset. The underlying cause of most cases of human narcolepsy is a loss of neurons that produce hypocretin (Hcrt, also known as orexin). These cells normally serve to drive and synchronize the activity of monoaminergic and cholinergic cells. Sleepiness results from the reduced activity of monoaminergic, cholinergic and other cells that are normally activated by Hcrt neurons, as well as from the loss of Hcrt itself. Cataplexy is caused by an episodic loss of activity in noradrenergic cells that support muscle tone, and a linked activation of a medial medullary cell population that suppresses muscle tone. Current treatments for narcolepsy include stimulants to combat sleepiness and antidepressants to reduce cataplexy. Sodium oxybate produces both reductions in cataplexy and improved waking alertness. Future treatments are likely to include Hcrt or Hcrt agonists to reverse the underlying neurochemical deficit.

Key Points

  • Narcolepsy is characterized by excessive daytime sleepiness, disrupted night-time sleep, cataplexy, sleep paralysis, hypnagogic hallucinations, and short latency from waking to the initiation of rapid eye movement sleep

  • Cataplexy most commonly occurs during behaviors accompanied by strong, positive emotions, with laughter being the most common trigger

  • In 2000, two simultaneously published papers determined that most human narcolepsy was linked to a loss of hypothalamic cells containing hypocretin (Hcrt, also known as orexin)

  • In the brain, Hcrt somata are found only in the hypothalamus; Hcrt cells project widely throughout the brain, and generally have excitatory effects on their postsynaptic cells

  • In brains from people with narcolepsy, only 10%, on average, of the normal numbers of Hcrt cells are seen; the loss of tonic Hcrt drive to histaminergic, dopaminergic, cholinergic and thalamic cells makes it difficult to sustain waking periods

  • The possibility that most cases of narcolepsy are autoimmune in etiology has led to several recent attempts to treat newly diagnosed narcolepsy by manipulating the immune system

  • There is evidence that Hcrt replacement therapy has the potential for reversing many of the symptoms of narcolepsy; several symptomatic treatments for narcolepsy are also available

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Figure 1: An autoimmune hypothesis of HLA DQB1*0602-linked narcolepsy with cataplexy.
Figure 2: Hypothesized role of hypocretin (Hcrt) cells in the cataplexy and sleepiness of narcolepsy.

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Acknowledgements

Supported by US PHS grants NS14610, MH64109 and the Medical Research Service of the Department of Veterans Affairs. We thank Adam Siegel for drawing Figure 1.

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Authors and Affiliations

  1. University of California, Los Angeles (UCLA)

    Jerome M Siegel

  2. Chief of Neurobiology Research at the VA Greater Los Angeles Healthcare System, CA, USA

    Jerome M Siegel

  3. postdoctoral fellow at UCLA, CA, USA

    Lisa N Boehmer

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Correspondence to Jerome M Siegel.

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Siegel, J., Boehmer, L. Narcolepsy and the hypocretin system—where motion meets emotion. Nat Rev Neurol 2, 548–556 (2006). https://doi.org/10.1038/ncpneuro0300

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