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.

Fig. 1 |. Wake-promoting and cataplexy-suppressing orexin pathways.

a | Orexin neurons (dark blue) maintain wake by exciting various wake-promoting neurons (green), including those in the cortex, basal forebrain (BF), tuberomammillary nucleus (TMN), pedunculopontine and laterodorsal tegmental nuclei (PPT–LDT), dorsal raphe (DR) and locus coeruleus (LC). Orexin neurons may also undergo auto-excitation, helping drive sustained activity in the orexin neurons and their targets. b | Normally, orexin neurons (dark blue) block the occurrence of muscle paralysis during wake by activating rapid eye movement (REM) sleep-suppressing regions (green), such as neurons in the ventral lateral periaqueductal grey and lateral pontine tegmentum (vlPAG–LPT), DR and LC. All these nuclei inhibit the sublaterodorsal nucleus (SLD), a region which, during REM sleep, drives muscle paralysis by activating GABAergic premotor neurons that inhibit motor neurons (purple). With strong emotional stimuli, signals from the medial prefrontal cortex (mPFC) probably activate orexin neurons and neurons in the central nucleus of the amygdala, which have opposing effects on the vlPAG–LPT, DR and LC. However, in narcolepsy, the excitatory drive from the orexin neurons is absent, and signals from the amygdala can inhibit these REM sleep-suppressing regions, enabling activity in the SLD and resulting in cataplexy.

Fig. 2 |. Inputs and outputs of the orexin neurons.

The orexin neurons are influenced by signals related to sleep–wake states, circadian phase, motivational cues and visceral cues such as hunger or thirst, and they innervate many brain regions. Their activity ultimately results in long periods of wakefulness, suppression and regulation of rapid eye movement (REM) sleep, enhanced responses to rewards, increased locomotion and increased autonomic tone. In addition to the orexin neuropeptides, which bind to orexin 1 receptors (OX1Rs; red circles) and OX2Rs (dark blue circles), orexin neurons also release the fast-acting neurotransmitter glutamate and possibly dynorphin. This pattern of connections highlights how the orexin neurons are uniquely positioned to integrate a wide variety of signals to acutely and persistently promote many aspects of arousal. Arc, arcuate nucleus; BF, basal forebrain; DMH, dorsomedial nucleus of the hypothalamus; DR, dorsal raphe; LC, locus coeruleus; LPT, lateral pontine tegmentum; NAc, nucleus accumbens; NST, nucleus of the solitary tract; PB, parabrachial nucleus; POA, preoptic area; PVH, paraventricular nucleus of the hypothalamus; SCN, suprachiasmatic nucleus; TMN, tuberomammillary nucleus; vlPAG, ventrolateral periaqueductal grey; VTA, ventral tegmental area.

Fig. 3 |. A model for T cell-mediated killing of the orexin neurons in narcolepsy.

In a possible model of T cell-mediated killing of orexin neurons, an antigen-presenting cell (APC) first takes up a pathogen and presents fragments of pathogen proteins to a naive CD4⁺ T cell using a major histocompatibility complex (MHC) class II molecule, perhaps DQB1*0602. The naive CD4⁺ T cell may secrete cytokines (circles) to help clear the infection. Memory CD4⁺ T cells are formed from the initial infection. Fever may promote the migration of pathogen-specific CD4⁺ T cells across the blood–brain barrier (BBB). The activated memory CD4⁺ T cell cross-recognizes fragments of prepro-orexin with a similar epitope as the pathogen peptide and secretes cytokines that promote destruction of the orexin neurons. Genes for which certain alleles are known to increase the risk of developing narcolepsy related to this model of T cell-mediated killing of orexin neurons are illustrated at their respective sites of action. TCR, T cell receptor.