Summary: According to a new study, melatonin works by suppressing neurons that keep you awake and alert. The findings could pave the way for new treatments for insomnia.
Source: University of Missouri Columbia.
An estimated 50 to 70 million Americans have some type of sleep disorder, according to the National Sleep Foundation. Some turn to melatonin supplements to help them fall asleep. Melatonin is a hormone known to promote sleep, but its underlying mechanisms are unknown. Now, researchers from the University of Missouri School of Medicine have discovered how melatonin suppresses neurons in the brain that keeps you awake and alert. These findings could lead to new therapies for those who suffer from insomnia.
“We as a society are losing sleep because we are working too hard, and it’s causing a variety of health concerns,” said Mahesh Thakkar, PhD, professor and director of research in the MU School of Medicine’s Department of Neurology and lead author of the study. “We often don’t even think about sleep or consider it important. However, there is nothing more important than sleep. We need to focus on therapies that can help you have quality sleep, not just sleep.”
Using a mouse model, Thakkar’s research found that melatonin infused in the brain at dark — when the mice are awake and active — increased sleep and reduced wakefulness by suppressing specific neurons that stimulate the brain to wake up. Thakkar also discovered that blocking melatonin receptors in the brain at bedtime significantly increased wakefulness. The experiments singled out one receptor, MT1, as the mechanism via which melatonin acts to inhibit the specific orexin neurons that wake you up. This discovery could help lead to medications that target only the MT1 receptor instead of multiple receptors, which could lead to fewer side effects for those who take sleep-promoting drugs.
“Melatonin has been used as a sleep drug for many years, but people didn’t know how it worked,” Thakkar said. “Our research suggests that if you target the melatonin MT1 receptor, you will get the most sleep with minimal side effects.”
In addition to Thakkar, the study authors include Pradeep K. Sahota, MD, chair of neurology at the MU School of Medicine; and Rishi Sharma, PhD, assistant research professor of neurology at the MU School of Medicine. Their study, “Melatonin Promotes Sleep in Mice by Inhibiting Orexin Neurons in the Perifornical Lateral Hypothalamus,” was recently published by the Journal of Pineal Research. Research reported in this publication was supported by the Harry S. Truman Memorial Veterans’ Hospital and the Department of Veterans Affairs Merit Research Award number I01BX002661. The authors of the study declare that they have no conflicts of interest. The content is solely the responsibility of the authors and does not necessarily represent the official views of the funding agencies.
Funding: The study is funded by the Harry S. Truman Memorial Veterans’ Hospital, Department of Veterans Affairs Merit Research Award.
Source: Eric Maze – University of Missouri Columbia
Publisher: Organized by NeuroscienceNews.com.
Image Source: NeuroscienceNews.com image is in the public domain.
Original Research: Abstract for “Melatonin promotes sleep in mice by inhibiting orexin neurons in the perifornical lateral hypothalamus” by Rishi Sharma, Pradeep Sahota, and Mahesh M. Thakkar in Journal of Pineal Research. Published April 14 2018.
Melatonin promotes sleep in mice by inhibiting orexin neurons in the perifornical lateral hypothalamus
Melatonin promotes sleep. However, the underlying mechanisms are unknown. Orexin neurons in the perifornical lateral hypothalamus (PFH) are pivotal for wake promotion. Does melatonin promote sleep by inhibiting orexin neurons? We used C57BL/6J mice and designed 4 experiments to address this question. Experiment 1 used double‐labeled immunofluorescence and examined the presence of melatonin receptors on orexin neurons. Second, mice, implanted with bilateral guides targeted toward PFH and sleep‐recording electrodes, were infused with melatonin (500 pmole/50 nL/side) at dark onset (onset of active period), and spontaneous bouts of sleep‐wakefulness were examined. Third, mice, implanted with bilateral guides into the PFH, were infused with melatonin (500 pmole/50 nL/side) at dark onset and euthanized 2 hours later, to examine the activation of orexin neurons using c‐Fos expression in orexin neurons. Fourth, mice, implanted with PFH bilateral guides and sleep‐recording electrodes, were infused with melatonin receptor antagonist, luzindole (10 pmol/50 nL/side), at light onset (onset of sleep period), and spontaneous bouts of sleep‐wakefulness were examined. Our results suggest that orexin neurons express MT1, but not MT2 receptors. Melatonin infusion into the PFH, at dark onset, site‐specifically and significantly increased NREM sleep (43.7%, P = .003) and reduced wakefulness (12.3%, P = .013). Local melatonin infusion at dark onset inhibited orexin neurons as evident by a significant reduction (66%, P = .0004) in the number of orexin neurons expressing c‐Fos. Finally, luzindole infusion‐induced blockade of melatonin receptors in PFH at sleep onset significantly increased wakefulness (44.1%, P = .015). Based on these results, we suggest that melatonin may act via the MT1 receptors to inhibit orexin neurons and promote sleep.