Illuminating Narcolepsy’s Neural Pathways

Sleep and wakefulness are carefully balanced by a network of brain regions. Yet for many years, scientists couldn’t pinpoint exactly which neurons regulated sleep state transitions.

New research tools and a deeper understanding of brain signaling have led to new discoveries in dopamine and norepinephrine signaling, offering novel insights into the sleep-wake cycle and cataplexy and paving the way for more targeted treatments in narcolepsy.

Narcolepsy affects approximately one in every 2,000 individuals in the U.S.¹ It’s a prevalent and debilitating REM sleep-related disorder with symptoms that generally develop in adolescence.

These symptoms include excessive daytime sleepiness, disrupted nighttime sleep, and in people with narcolepsy type 1, cataplexy—the inappropriate intrusion of REM sleep muscle paralysis during wakefulness, often in response to strong emotions.

The condition takes a significant toll, on a personal and societal level, leading to reduced productivity and higher health care costs. However, the neural mechanisms that contribute to disrupted sleep and cataplexy in patients with narcolepsy are still not fully known.

Numerous brain regions have been investigated over the years, but recent interest has centered on the monoaminergic system, which is comprised of norepinephrine, dopamine, serotonin, and histamine neurotransmitter pathways. In particular, new research is looking at midbrain dopamine neurons in the ventral tegmental area (a brain region important for processing positive emotions and rewards) and brainstem norepinephrine neurons in the locus coeruleus (a small nucleus deep in the brainstem involved in attention and locomotion).

Evidence suggests an important role for dopamine and norepinephrine not only in sleepiness, but in other symptoms of narcolepsy as well. In this article, we will briefly review studies on the neural regulation of sleep states and highlight recent advances in the field, with a focus on narcolepsy.

Landmark Findings in the Neurobiology of Sleep and Narcolepsy

A major clue into the inner workings of the sleep-wake cycle came in the late 1990s—when two independent labs discovered a hypothalamic peptide called orexin (also known as hypocretin) that was key in maintaining wakefulness.^2–4

Shortly after, a mouse model was developed in which this peptide was eliminated, and these mice experienced sleepiness, fragmented sleep, and sudden bouts of immobility during wakefulness.⁵ These phenotypes bore a striking resemblance to the human sleep disorder narcolepsy type I, and indeed, researchers soon confirmed that human narcolepsy results from the loss of hypothalamic orexin.⁶

Decades of research had laid the groundwork for this important breakthrough.

As many as 50 years ago, neuroscientists were studying the neural mechanisms of narcolepsy using animal models. These early, pioneering studies made use of a naturally occurring canine model of narcolepsy to explore the brain regions and circuits involved in sleepiness and cataplexy. By recording the activity of individual neurons in the brain or manipulating circuits using specific drugs as these dogs slept and had episodes of cataplexy, researchers identified a potential role for presumed dopamine- and norepinephrine-releasing neurons.

Pharmacological manipulation of specific dopamine receptors—including direct injections into the ventral tegmental area—was shown to alter the frequency of cataplexy episodes.^7–9 Recordings of presumed norepinephrine-containing neurons in the brainstem revealed that their activity was high during normal waking but dropped to near zero during cataplexy.¹⁰ Furthermore, by artificially increasing the amount of norepinephrine binding to the brain’s norepinephrine receptors, researchers showed that cataplexy could be powerfully suppressed.¹¹

New Frontiers in Neuroscience

These landmark findings provided ample support that dopamine and norepinephrine systems play a role in the regulation of cataplexy, but many more specific tools and approaches have become available to neuroscientists in the decades since these studies were completed.

Genetically engineered murine models

Murine models offer a significant advantage over canine models: the ability to precisely target specific neuronal populations. Thanks to tools that enable selective modification of aspects of the mouse genome, researchers can manipulate brain circuits with a level of specificity that was not previously possible.

Several mouse models of narcolepsy now exist—developed either by disrupting the orexin protein/receptor, or by eliminating orexin-synthesizing neurons. These models reliably replicate many key aspects of human narcolepsy. Just as important, these models enable the use of advanced neuroscience techniques that have dramatically increased the resolution and specificity with which we can record and manipulate neural circuits in mice. (See Figure 1.)

 

Optogenetics and fiber photometry

Perhaps the most impactful neuroscience innovation of this century was the advent of optogenetics.¹² This technique involves delivering a light-gated channel to neuronal populations of interest. When illuminated with light of a specific wavelength, these channels can be used to activate or suppress activity in targeted neurons. Unlike pharmacological manipulations, which can last several hours after an injection and often impact the entire brain, optogenetics allows for exquisite temporal and spatial specificity when manipulating neural circuits.

Another technique called fiber photometry also involves using light, not to activate or inhibit neurons, but instead to record their endogenous activity.¹³ Initially used to record neuron activity, fiber photometry has since been adapted to allow recording of transmitter release from neurons, including specialized biosensors that have been developed to record dopamine and norepinephrine release.^14-15

These two approaches, combined with good mouse models of narcolepsy, allow researchers to identify neural circuits that contribute to sleepiness and cataplexy with unprecedented precision.

Monoaminergic Regulation of Sleep and Cataplexy

Using these new approaches, our group and others have recently uncovered novel insights into how the dopamine and norepinephrine systems influence sleep and cataplexy. As noted above, the dopamine system has long been implicated in reward and positive emotional stimuli, especially when dopamine is released into the limbic system—a collection of brain regions related to emotion.

Both REM sleep and cataplexy have emotional components: REM sleep is when vivid dreaming occurs, and cataplexy is often triggered by strong emotions. These connections have led to the hypothesis that dopamine release in the limbic system may promote either REM sleep or cataplexy. In a pivotal 2022 study, researchers found that dopamine is released into the amygdala immediately prior to REM sleep in healthy mice, and that suppressing dopamine release in this region reduced the total amount of time spent in REM sleep.¹⁶ These findings were extended to narcoleptic mice, in which increasing dopamine release in the amygdala promoted cataplexy.

Using fiber photometry combined with a dopamine biosensor, research from our lab showed that dopamine release in the nucleus accumbens—a different region of the limbic system—gradually increases over the course of NREM sleep bouts that end in REM sleep.¹⁷ Dopamine release during NREM sleep was also sensitive to REM sleep pressure, with elevated dopamine levels observed after the mice were deprived of REM sleep. Furthermore, optogenetic inhibition of dopamine release decreased the frequency of bouts of REM sleep.

In narcoleptic mice, we found that dopamine release in the nucleus accumbens increased prior to cataplexy and remained elevated during the episode.¹⁸ Increasing dopamine release in this region was also sufficient to increase cataplexy propensity. These findings support the theory that emotional stimuli may induce cataplexy by increasing dopamine release in regions of the brain that regulate emotions. (See Figures 2 and 3.)

Recent studies using fiber photometry have demonstrated that the activity of monoaminergic neurons change during REM sleep and cataplexy. Dopamine (DA)activity increases during REM sleep and cataplexy, while norepinephrine (NE) activity decreases during these states.

Investigating Norepinephrine’s Role in Regulating REM Sleep

Although norepinephrine has traditionally been considered a wake-promoting neurotransmitter, recent studies have challenged this view by demonstrating that norepinephrine is also released during NREM sleep and may specifically suppress entrances into REM sleep.^19–21 Our lab is currently investigating the function of norepinephrine release in midbrain and brainstem regions that regulate REM sleep.

Preliminary work from our group has found that norepinephrine release in the midbrain is elevated during wakefulness and NREM sleep, but suppressed during both REM sleep and cataplexy. In line with earlier findings in the canine model described above, this data greatly extends our understanding by:

1. Measuring norepinephrine release directly, rather than inferring it from the activity of presumed norepinephrine-containing neurons, and
2. Having the spatial specificity to start to tease apart the brain regions downstream of norepinephrine-containing neurons that mediate the effect on cataplexy.

In follow-up studies, we used optogenetic activation of norepinephrine-containing neurons in the brainstem to powerfully suppress entrances into cataplexy. These findings are exciting as they point toward a specific role for midbrain norepinephrine signaling in regulating both REM sleep and cataplexy.

Clinical Relevance for Targeted Treatments

One of the more effective treatments for both sleepiness and cataplexy in patients with narcolepsy is sodium oxybate. Due to its relatively short half-life of 40 minutes, sodium oxybate is generally given once before bed and again during the night. While its sustained effect is to promote restful NREM sleep and reduce cataplexy during wakefulness, an interesting phenomenon occurs when sodium oxybate is first administered: it can actually promote both REM sleep and cataplexy.²² The mechanisms underlying this initial increase and subsequent decrease are largely unknown, but recent findings by our group and others may help to clarify this discrepancy.

Sodium oxybate is believed to function as a weak GABA-B receptor agonist.²³ Norepinephrine neurons in the locus coeruleus can be inhibited by GABA, specifically through activation of GABA-B receptors.²⁴ Given that our research team and others have found that norepinephrine release can potently suppress REM sleep and cataplexy, one possibility is sodium oxybate initially suppresses norepinephrine neuron activity, promoting both restful NREM and REM sleep. However, as the effect of the drug wears off, the subsequent rebound of norepinephrine release could function to both maintain wakefulness and suppress cataplexy.

Another promising class of treatments includes histamine H₃ receptor inverse agonists. Histamine generally promotes arousal, and H₃ receptors are inhibitory autoreceptors on histamine neurons that function to decrease their activity.²⁵ Inverse agonism of these receptors results in increased histamine release, which in turn stimulates the monoaminergic system, including norepinephrine neurons in the locus coeruleus.

Similar to oxybate, the net result of this manipulation is likely an increase in norepinephrine release, thus promoting wakefulness and suppressing cataplexy. While the specific circuits and mechanisms of action by which these drugs reduce the burden of narcolepsy have yet to be discovered, these findings provide valuable insights into targeted treatments going forward.

Conclusions

In the past 50 years, great strides have been made in understanding the genetics, neurochemistry, and specific brain circuits that aggravate or alleviate symptoms of narcolepsy. In particular, recent studies highlighting the role of dopamine release in the limbic system and norepinephrine activity in REM sleep and cataplexy have advanced the field considerably.

These findings shed light on the specific circuits through which monoaminergic nuclei may signal to regulate sleepiness and cataplexy. Furthermore, their relevance may extend beyond narcolepsy, informing our understanding of sleep regulation in healthy individuals as well as sleep disturbances in conditions such as Parkinson’s and REM sleep behavior disorder.

These same circuits are also involved in attention, offering a possible explanation for why poor-quality sleep results in decreased daytime focus. While many questions remain about the neurobiology of narcolepsy and sleep disorders in general, these findings represent a meaningful and significant step toward a more complete understanding of the neural circuits that govern sleep behavior.

 

Brandon A. Toth is a fifth-year PhD student in the Neuroscience Graduate Program at the University of Michigan.

Christian R. Burgess, PhD, is an assistant professor of Molecular and Integrative Physiology and is affiliated with the Michigan Neuroscience Institute at the University of Michigan.

 

 

Source: SleepWorld Magazine May/June 2025

References

1. Scammell TE. Narcolepsy. N Engl J Med. 2015;373(27):2654-62. doi: 10.1056/NEJMra1500587.
2. Sakurai T, Amemiya A, Ishii M, et al. Orexins and orexin receptors: a family of hypothalamic neuropeptides and G protein-coupled receptors that regulate feeding behavior. Cell. 1998;92(4):573-585. doi: 10.1016/s0092-8674(00)80949-6.
3. de Lecea L, Kilduff TS, Peyron C, et al. The hypocretins: hypothalamus-specific peptides with neuroexcitatory activity. Proc Natl Acad Sci U S A. 1998;95(1):322-7. doi: 10.1073/pnas.95.1.322.
4. Hagan JJ, Leslie RA, Patel S,sleep world figureet al. Orexin A activates locus coeruleus cell firing and increases arousal in the rat. Proc Natl Acad Sci U S A. 1999;96(19):10911-6. doi: 10.1073/pnas.96.19.10911.
5. Chemelli RM, Willie JT, Sinton CM, et al. Narcolepsy in orexin knockout mice: molecular genetics of sleep regulation. Cell. 1999;98(4):437-51. doi: 10.1016/s0092-8674(00)81973-x.
6. Nishino S, Ripley B, Overeem S, Lammers GJ, Mignot E. Hypocretin (orexin) deficiency in human narcolepsy. Lancet. 2000;355(9197):39-40. doi: 10.1016/S0140-6736(99)05582-8.
7. Honda K, Riehl J, Mignot E, Nishino S. Dopamine D₃ agonists into the substantia nigra aggravate cataplexy but do not modify sleep. Neuroreport. 1999;10(17):3717-24. doi: 10.1097/00001756-199911260-00046.
8. Okura M, Riehl J, Mignot E, Nishino S. Sulpiride, a D2/D3 blocker, reduces cataplexy but not REM sleep in canine narcolepsy. Neuropsychopharmacology. 2000;23(5):528-38. doi: 10.1016/S0893-133X(00)00140-8.
9. Reid MS, Tafti M, Nishino S, Sampathkumaran R, Siegel JM, Mignot E. Local administration of dopaminergic drugs into the ventral tegmental area modulates cataplexy in the narcoleptic canine. Brain Res. 1996;733(1):83-100. doi: 10.1016/0006-8993(96)00541-0.
10. Wu MF, Gulyani SA, Yau E, Mignot E, Phan B, Siegel JM. Locus coeruleus neurons: cessation of activity during cataplexy. Neuroscience. 1999;91(4):1389-99. doi: 10.1016/s0306-4522(98)00600-9.
11. Mignot E, Renaud A, Nishino S, Arrigoni J, Guilleminault C, Dement WC. Canine cataplexy is preferentially controlled by adrenergic mechanisms: evidence using monoamine selective uptake inhibitors and release enhancers. Psychopharmacology (Berl). 1993;113(1):76-82. doi: 10.1007/bf02244337.
12. Yizhar O, Fenno LE, Davidson TJ, Mogri M, Deisseroth K. Optogenetics in neural systems. Neuron. 2011;71(1):9-34. doi: 10.1016/j.neuron.2011.06.004.
13. Simpson EH, Akam T, Patriarchi T, et al. Lights, fiber, action! A primer on in vivo fiber photometry. Neuron. 2024;112(5):718-39. doi: 10.1016/j.neuron.2023.11.016.
14. Patriarchi T, Cho JR, Merten K, et al. Ultrafast neuronal imaging of dopamine dynamics with designed genetically encoded sensors. Science. 2018;360(6396): eaat4422. doi: 10.1126/science.aat4422.
15. Feng J, Zhang C, Lischinsky JE, et al. A genetically encoded fluorescent sensor for rapid and specific in vivo detection of norepinephrine. Neuron. 2019;102(4):745-761.e8. doi: 10.1016/j.neuron.2019.02.037.
16. Hasegawa E, Miyasaka A, Sakurai K, Cherasse Y, Li Y, Sakurai T. Rapid eye movement sleep is initiated by basolateral amygdala dopamine signaling in mice. Science. 2022;375(6584):994-1000. doi: 10.1126/science.abl6618.
17. Toth BA, Burgess CR. Phasic dopamine release in the nucleus accumbens influences REM sleep timing. J Neurosci. 2025;45(9):e1374242024. doi: 10.1523/JNEUROSCI.1374-24.2024.
18. Toth BA, Chang KS, Fechtali S, Burgess CR. Dopamine release in the nucleus accumbens promotes REM sleep and cataplexy. iScience. 2023;26(9):107613. doi: 10.1016/j.isci.2023.107613.
19. Aston-Jones G, Bloom FE. Activity of norepinephrine-containing locus coeruleus neurons in behaving rats anticipates fluctuations in the sleep-waking cycle. J Neurosci. 1981;1(8):876-86. doi: 10.1523/JNEUROSCI.01-08-00876.1981.
20. Osorio-Forero A, Cardis R, Vantomme G, et al. Noradrenergic circuit control of non-REM sleep substates. Curr Biol. 2021;31(22):5009-5023.e7. doi: 10.1016/j.cub.2021.09.041.
21. Kjaerby C, Andersen M, Hauglund N, et al. Memory-enhancing properties of sleep depend on the oscillatory amplitude of norepinephrine. Nat Neurosci. 2022;25(8):1059-70. doi: 10.1038/s41593-022-01102-9.
22. Mamelak M. Sleep, narcolepsy, and sodium oxybate. Curr Neuropharmacol. 2022;20(2):272-91. doi: 10.2174/1570159X19666210407151227.
23. Vienne J, Bettler B, Franken P, Tafti M. Differential effects of GABAB receptor subtypes, {gamma}-hydroxybutyric Acid, and Baclofen on EEG activity and sleep regulation. J Neurosci. 2010;30(42):14194-204. doi: 10.1523/JNEUROSCI.3145-10.2010.
24. Wang HY, Kuo ZC, Fu YS, Chen RF, Min MY, Yang HW. GABAB receptor-mediated tonic inhibition regulates the spontaneous firing of locus coeruleus neurons in developing rats and in citalopram-treated rats. J Physiol. 2015;593(1):161-80. doi: 10.1113/jphysiol.2014.281378.
25. Scammell TE, Jackson AC, Franks NP, Wisden W, Dauvilliers Y. Histamine: neural circuits and new medications. Sleep. 2019;42(1):zsy183. doi: 10.1093/sleep/zsy183.