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The neurobiological basis of narcolepsy

Abstract

Narcolepsy is the most common neurological cause of chronic sleepiness. The discovery about 20 years ago that narcolepsy is caused by selective loss of the neurons producing orexins (also known as hypocretins) sparked great advances in the field. Here, we review the current understanding of how orexin neurons regulate sleep–wake behaviour and the consequences of the loss of orexin neurons. We also summarize the developing evidence that narcolepsy is an autoimmune disorder that may be caused by a T cell-mediated attack on the orexin neurons and explain how these new perspectives can inform better therapeutic approaches.

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Fig. 1: Wake-promoting and cataplexy-suppressing orexin pathways.
Fig. 2: Inputs and outputs of the orexin neurons.
Fig. 3: A model for T cell-mediated killing of the orexin neurons in narcolepsy.

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Acknowledgements

The authors acknowledge support from the US National Institutes of Health grants P01 HL095491, R21 NS099787 and R01 NS106032.

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Nature Reviews Neuroscience thanks B. Kornum, T. Sakurai and the other anonymous reviewer(s) for their contribution to the peer review of this work.

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Glossary

Hypnopompic and hypnagogic hallucinations

Vivid, sometimes frightening, dream-like hallucinations that occur when falling asleep (hypnopompic) or immediately after waking (hypnagogic).

Sleep paralysis

An inability to move when falling asleep or immediately after waking.

Cataplexy

Muscle weakness or full paralysis triggered by strong, generally positive, emotions.

REM sleep behaviour disorder

A disorder characterized by impaired motor inhibition during rapid eye movement sleep, resulting in enactment of dreams.

Hypersomnia

An abnormally high total amount of sleep over 24 hours.

Status cataplecticus

A prolonged period of moderate to severe weakness with low muscle tone, usually without emotional triggers.

Major histocompatibility complex

(MHC). A set of immune molecules that bind pathogen-derived antigens and display them on the surface of antigen-presenting cells to promote acquired immune responses.

Human leukocyte antigen (HLA) allele

An allele encoding a human major histocompatibility complex molecule.

Molecular mimicry

A mechanism of autoimmunity in which a foreign antigen is structurally similar to ‘self’-peptides, such that immune cells targeting a pathogen accidentally target healthy tissue.

Linkage disequilibrium

When the observed frequency of two alleles at two loci occurring together is more frequent than would occur by chance.

Myenteric plexus

The network of sensory and motor neurons that control gut secretions and motility.

Regulatory T cells

(Treg cells). T cells that maintain tolerance to self-antigens by downregulating the activity of effector T cells using anti-inflammatory cytokines and cell-to-cell inhibition.

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Mahoney, C.E., Cogswell, A., Koralnik, I.J. et al. The neurobiological basis of narcolepsy. Nat Rev Neurosci 20, 83–93 (2019). https://doi.org/10.1038/s41583-018-0097-x

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