A circuit perspective on narcolepsy

Abstract

The sleep disorder narcolepsy is associated with symptoms related to either boundary state control that include excessive daytime sleepiness and sleep fragmentation, or rapid eye movement (REM) sleep features including cataplexy, sleep paralysis, hallucinations, and sleep-onset REM sleep events (SOREMs). Although the loss of Hypocretin/Orexin (Hcrt/Ox) peptides or their receptors have been associated with the disease, here we propose a circuit perspective of the pathophysiological mechanisms of these narcolepsy symptoms that encompasses brain regions, neuronal circuits, cell types, and transmitters beyond the Hcrt/Ox system. We further discuss future experimental strategies to investigate brain-wide mechanisms of narcolepsy that will be essential for a better understanding and treatment of the disease.

Keywords: cataplexy; hypocretins/orexins; narcolepsy; neural circuits.

Figure 1:

Pathophysiology of narcolepsy. (A–D) Hypocretin and MCH mRNA expression in the hypothalamus of a control subject and a person with narcolepsy. Preprohypocretin transcripts are detected in the hypothalamus of a control (B) but not in a narcolepsy (A) subject, while MCH transcripts are detected, intermingled with hypocretin in both control (D) and narcolepsy (C) samples. f, fornix scale bars = 10 mm. Adapted from Peyron et al. (2000). (E) Strong, positive emotions many activate neurons in the medial prefrontal cortex (mPFC) that excite neurons making orexin and MCH as well as neurons in the amygdala. Normally, the orexin neurons would then excite atonia-suppressing neurons of the ventrolateral periaqueductal gray/lateral pontine tegmentum (vlPAG/LPT), but in the absence of orexins, the inhibitory effects of MCH and the amygdala are unopposed. Lacking inhibition from the vlPAG/LPT, the sublaterodorsal nucleus (SLD) can then inhibit motor neurons via GABA and glycine-containing neurons of the medial medulla. Norepinephrine from the locus coeruleus (LC) normally inhibits REM sleep and cataplexy, and the LC is probably inhibited during cataplexy, perhaps via the amygdala and MCH neurons. This model is built upon research derived from many labs, but its basic components are still debated and remain to be definitively demonstrated. Pathways active during cataplexy are shown with solid lines; pathways inactive during cataplexy are shown with dashed lines. Inhibitory pathways are purple; excitatory pathways are green.

Figure 2:

Circuit perspective of narcolepsy. Schematic representation of the physiological elements underlying the symptoms of narcolepsy, including excessive daytime sleepiness, sleep fragmentation, cataplexy, hypnagogic hallucinations, SOREMS and sleep paralysis. These are divided into symptoms related to boundary state control (highlighted in the green box) or REM sleep (highlighted in the blue box) and are distributed across the sleep–wake cycles (top part of the figure). The bottom part of the figure highlights possible mechanisms involving neural circuits of boundary state control (top) and REM sleep (bottom). In this schematic representation, primary circuit hubs controlling sleep wake state (top) or REM-related brain activity or phenomena (bottom) are represented by large dots connected to each other; smaller dots represent secondary output circuits. Color coding indicates active (red) or inactive (green) networks and pathways. Some of the symptoms of narcolepsy are thought to result from a weak boundary state control. For example, in the absence of excitatory Hcrt/Ox drive, excessive daytime sleepiness could arise from weak or inconsistent activity of wake-promoting systems, or inappropriate intrusion of NREM sleep-promoting regions. Similarly, sleep fragmentation could result from uncoordinated activity of wake-promoting neurons during sleep. Abnormal activity in REM sleep circuits may produce other symptoms of narcolepsy including cataplexy during wakefulness, hypnagogic hallucination during NREM sleep, and SOREMS or sleep paralysis during REM sleep. In the context of this perspective, cataplexy may result from overactivity of REM sleep circuits during wakefulness (hyperactivity model) or hypoactivity of REM-suppressing circuits (hypoactivity model) and the activation of brain circuits governing theta rhythm or muscle atonia. Hypnagogic hallucinations occur at the transition from wakefulness to sleep and may result from the activation of REM sleep circuits that promote dreaming/imagery and sometimes muscle atonia (paralysis). SOREMs implicate a comprehensive activation of REM sleep circuits, including those responsible for theta rhythms, muscle atonia, eye movements, dreaming/imagery and the autonomic system. Finally, hypnopompic hallucinations and sleep paralysis may result from the co-activation of both wake and REM circuits, in particular those involved in muscle atonia, dreaming/imagery and the autonomic system.