For about 165,000 people in the United States1, staying awake during the day is a tall order. Individuals with narcolepsy often fall asleep with little warning. But the condition involves far more than just tiredness. It can affect every aspect of life. Around 70 per cent of people with narcolepsy suffer with cataplexy (brief episodes of sudden loss of muscle strength or tone, often brought on by strong emotions)2, and some people with narcolepsy experience hallucinations (vivid dream-like experiences while falling asleep or waking up), and sleep paralysis (the temporary inability to move or speak during sleep-wake transitions). “Many people with narcolepsy feel the same way that you and I would if we’d been up all night,” says Thomas Scammell, a neurologist from Beth Israel Deaconess Medical Center, Boston Children’s Hospital, and Harvard Medical School. “No amount of coffee will keep them awake. They struggle to get through the day.” Doctors first recognized narcolepsy in the 1870s, but for more than a century, researchers had no idea what was causing chronic sleepiness and ‘sleep attacks’ in these individuals, Scammell explains. It was clear narcolepsy was a disruption of sleep-wake stability, so many experts suspected a problem in the hypothalamus—a key sleep-wake regulating center of the brain. But the confirmation didn’t come until the late 1990s, when two groups of scientists simultaneously discovered peptide neurotransmitters in cells in the hypothalamus. One team, from the Scripps Research Institute in San Diego, dubbed them hypocretins. The other research group, from the University of Texas Southwestern, named them orexins. Soon afterwards, researchers found that mice lacking hypocretins dozed off frequently, in a pattern suggestive of chronic sleepiness. Scientists later showed that brains from individuals with narcolepsy had 85-95 per cent fewer hypocretin neurons than brains from control subjects3. “The discovery of what seemed like some fairly obscure neurotransmitters turned out to be remarkable for understanding narcolepsy,” says Scammell. “It was like the game Minesweeper, where every once in a while, you click on a tile and half the field opens up.” A wake-up call Scientists now understand that hypocretins are crucial for keeping us awake at the right time. They likely do so by activating other brain cells that promote wakefulness, says Scammell. Hypocretins also seem to regulate rapid eye-movement (REM) sleep, the sleep phase responsible for vivid dreams. In narcolepsy, the normal boundaries between sleep, wake, and dreams blur. “When dreaming in REM sleep, the body is entirely paralyzed,” says Scammell. “Therefore, for people living with narcolepsy, it can be chaotic, as the body paralysis and dreams can mix into wakefulness.” An absence of hypocretins might therefore explain why many people with this sleep disorder experience cataplexy, hallucinations, or sleep paralysis. One leading theory is that narcolepsy arises when the immune system mistakenly attacks hypocretin-producing brain cells in the hypothalamus4. But Scammell suspects hypocretin deficiency isn’t the sole explanation. In recent years, he and other researchers have studied another neurotransmitter, one that most people associate with allergies. Histamine might be better known for its role in allergies and itchiness, but it is also produced in the hypothalamus by brain cells adjacent to the hypocretin neurons. Histamine is deemed wake-promoting because drowsiness is a common side effect of certain anti-allergy medications that block histamine signalling, says Scammell. What’s more, the histamine neurons are generally active in wake states, and inactive during sleep. Histamine neurons promote wakefulness by activating neurons in the cortex that drive arousal and by inhibiting neurons that promote sleep. In addition, hypocretins strongly activate the histamine-producing neurons, which researchers believe may be a key mechanism for promoting wake and regulating sleep5. Research suggests that histamine, similar to hypocretin, helps stabilize sleep-wake states, so that each stage of slumber has clear boundaries. To demonstrate the importance of histamine in stabilizing wakefulness, one study found mice lacking histamine experienced more REM sleep and flipped more frequently between sleep and wake states than control animals6. Histamine and narcolepsy After studying the evidence, Scammell assumed that the brains of people with narcolepsy must be deficient in histamine, however, experiments to explore this hypothesis returned confusing results. Scammell’s laboratory found that brains from people with narcolepsy (from cadavers) contained 94 per cent more histamine neurons than brains from individuals without the sleep disorder7. In patients with severe narcolepsy, the increase was even more pronounced. “This was completely unpredicted,” says Scammell. “It was so bizarre that we actually went back and repeated the experiment to check again.” Long-time collaborator Jerome Siegel from UCLA replicated the experiments in his laboratory, getting the same baffling results8. The researchers were stumped. If histamine promotes wakefulness, then why did patients with more histamine-producing brain cells suffer from narcolepsy? “It’s possible that the cells are capable of synthesizing histamine, but they’re just not releasing adequate amounts,” Scammell suggests. His best guess is the brain might make more histamine to try and compensate for the low concentration of hypocretins, but that this compensation still isn’t enough to promote normal sleep and wakefulness. Some studies have supported this theory, finding a lower concentration of histamine in the cerebrospinal fluid of narcolepsy patients9. However, other similar studies have found no such difference10. Histamine has a very short half-life, which makes it challenging to measure in people, says Scammell, potentially explaining the contradictory findings. Even with these remaining challenges, the neurobiology of narcolepsy is coming into focus. “We know histamine is an important wake-promoting neurotransmitter,” says Scammell, adding that it has received far less attention than other brain systems involved in sleep. He hopes that shining a light on histamine’s role in stabilizing sleep-wake states will encourage further research and development, and ultimately improve the quality of life for people living with narcolepsy. There’s more to learn about the neurobiology behind narcolepsy. Enhance your understanding at KnowNarcolepsyHCP.com

References

Narcolepsy Fact Sheet. NIH Publication No. 17-1637. https://www.ninds.nih.gov/Disorders/Patient-Caregiver-Education/Fact-Sheets/Narcolepsy-Fact-Sheet Thorpy, M. & Dauvilliers, Y. Clinical and practical considerations in the pharmacologic management of narcolepsy. Sleep Med. 16(1):9-18 (2015). Thannickal TC, Moore RY, Nienhuis R, et al. Neuron. 27,469-474 (2000). Latorre, D., et al. Nature 562, 63–68 (2018). Huang, Z L et al. PNAS. 98,17 (2001). Parmentier R, Ohtsu H, Djebbara-Hannas Z et al. J Neurosci.22,7695-711 (2002). Valko PO, Gavrilov YV, Yamamoto M et al. Ann Neurol. 74, 794-804 (2013). John J, Thannickal TC, McGregor R et al. Ann Neurol. 74:786-93 (2013). Kanbayashi T, Kodama T, Kondo H et al. Sleep. 32,181-7 (2009). Croyal M, Dauvilliers Y, Labeeuw O et al. Anal Biochem 409, 28-36 (2011).

“Many people with narcolepsy feel the same way that you and I would if we’d been up all night,” says Thomas Scammell, a neurologist from Beth Israel Deaconess Medical Center, Boston Children’s Hospital, and Harvard Medical School. “No amount of coffee will keep them awake. They struggle to get through the day.”

Doctors first recognized narcolepsy in the 1870s, but for more than a century, researchers had no idea what was causing chronic sleepiness and ‘sleep attacks’ in these individuals, Scammell explains. It was clear narcolepsy was a disruption of sleep-wake stability, so many experts suspected a problem in the hypothalamus—a key sleep-wake regulating center of the brain. But the confirmation didn’t come until the late 1990s, when two groups of scientists simultaneously discovered peptide neurotransmitters in cells in the hypothalamus.

One team, from the Scripps Research Institute in San Diego, dubbed them hypocretins. The other research group, from the University of Texas Southwestern, named them orexins.

Soon afterwards, researchers found that mice lacking hypocretins dozed off frequently, in a pattern suggestive of chronic sleepiness. Scientists later showed that brains from individuals with narcolepsy had 85-95 per cent fewer hypocretin neurons than brains from control subjects3.

“The discovery of what seemed like some fairly obscure neurotransmitters turned out to be remarkable for understanding narcolepsy,” says Scammell. “It was like the game Minesweeper, where every once in a while, you click on a tile and half the field opens up.”

A wake-up call

Scientists now understand that hypocretins are crucial for keeping us awake at the right time. They likely do so by activating other brain cells that promote wakefulness, says Scammell. Hypocretins also seem to regulate rapid eye-movement (REM) sleep, the sleep phase responsible for vivid dreams.

In narcolepsy, the normal boundaries between sleep, wake, and dreams blur. “When dreaming in REM sleep, the body is entirely paralyzed,” says Scammell. “Therefore, for people living with narcolepsy, it can be chaotic, as the body paralysis and dreams can mix into wakefulness.” An absence of hypocretins might therefore explain why many people with this sleep disorder experience cataplexy, hallucinations, or sleep paralysis. One leading theory is that narcolepsy arises when the immune system mistakenly attacks hypocretin-producing brain cells in the hypothalamus4.

But Scammell suspects hypocretin deficiency isn’t the sole explanation. In recent years, he and other researchers have studied another neurotransmitter, one that most people associate with allergies. Histamine might be better known for its role in allergies and itchiness, but it is also produced in the hypothalamus by brain cells adjacent to the hypocretin neurons.

Histamine is deemed wake-promoting because drowsiness is a common side effect of certain anti-allergy medications that block histamine signalling, says Scammell. What’s more, the histamine neurons are generally active in wake states, and inactive during sleep. Histamine neurons promote wakefulness by activating neurons in the cortex that drive arousal and by inhibiting neurons that promote sleep. In addition, hypocretins strongly activate the histamine-producing neurons, which researchers believe may be a key mechanism for promoting wake and regulating sleep5.

Research suggests that histamine, similar to hypocretin, helps stabilize sleep-wake states, so that each stage of slumber has clear boundaries. To demonstrate the importance of histamine in stabilizing wakefulness, one study found mice lacking histamine experienced more REM sleep and flipped more frequently between sleep and wake states than control animals6.

Histamine and narcolepsy

After studying the evidence, Scammell assumed that the brains of people with narcolepsy must be deficient in histamine, however, experiments to explore this hypothesis returned confusing results.

Scammell’s laboratory found that brains from people with narcolepsy (from cadavers) contained 94 per cent more histamine neurons than brains from individuals without the sleep disorder7. In patients with severe narcolepsy, the increase was even more pronounced. “This was completely unpredicted,” says Scammell. “It was so bizarre that we actually went back and repeated the experiment to check again.” Long-time collaborator Jerome Siegel from UCLA replicated the experiments in his laboratory, getting the same baffling results8. The researchers were stumped. If histamine promotes wakefulness, then why did patients with more histamine-producing brain cells suffer from narcolepsy?

“It’s possible that the cells are capable of synthesizing histamine, but they’re just not releasing adequate amounts,” Scammell suggests. His best guess is the brain might make more histamine to try and compensate for the low concentration of hypocretins, but that this compensation still isn’t enough to promote normal sleep and wakefulness. Some studies have supported this theory, finding a lower concentration of histamine in the cerebrospinal fluid of narcolepsy patients9. However, other similar studies have found no such difference10. Histamine has a very short half-life, which makes it challenging to measure in people, says Scammell, potentially explaining the contradictory findings.

Even with these remaining challenges, the neurobiology of narcolepsy is coming into focus. “We know histamine is an important wake-promoting neurotransmitter,” says Scammell, adding that it has received far less attention than other brain systems involved in sleep. He hopes that shining a light on histamine’s role in stabilizing sleep-wake states will encourage further research and development, and ultimately improve the quality of life for people living with narcolepsy.

There’s more to learn about the neurobiology behind narcolepsy. Enhance your understanding at KnowNarcolepsyHCP.com

References

  • Narcolepsy Fact Sheet. NIH Publication No. 17-1637. https://www.ninds.nih.gov/Disorders/Patient-Caregiver-Education/Fact-Sheets/Narcolepsy-Fact-Sheet
  • Thorpy, M. & Dauvilliers, Y. Clinical and practical considerations in the pharmacologic management of narcolepsy. Sleep Med. 16(1):9-18 (2015).
  • Thannickal TC, Moore RY, Nienhuis R, et al. Neuron. 27,469-474 (2000).
  • Latorre, D., et al. Nature 562, 63–68 (2018).
  • Huang, Z L et al. PNAS. 98,17 (2001).
  • Parmentier R, Ohtsu H, Djebbara-Hannas Z et al. J Neurosci.22,7695-711 (2002).
  • Valko PO, Gavrilov YV, Yamamoto M et al. Ann Neurol. 74, 794-804 (2013).
  • John J, Thannickal TC, McGregor R et al. Ann Neurol. 74:786-93 (2013).
  • Kanbayashi T, Kodama T, Kondo H et al. Sleep. 32,181-7 (2009).
  • Croyal M, Dauvilliers Y, Labeeuw O et al. Anal Biochem 409, 28-36 (2011).