In the 1970s, scientists identified the part of the brain that controls circadian rhythms – the 24-hour processes that regulate our sleep and wake cycles and key body functions like hormone production, metabolism and blood pressure. But it has taken until now to identify precisely which cells in the master clock drive the underlying timekeeping.
In a new study published in the journal Neuron, researchers from the University of Texas (UT) Southwestern Medical Center in Dallas describe how they identified key cells within the suprachiasmatic nucleus (SCN) that are critical for determining circadian rhythms.
The researchers believe their findings could lead to new drugs to treat a range of disorders, including sleep problems like jet lag, neurological diseases like Alzheimer’s, psychiatric disorders such as depression, plus metabolism problems.
Circadian rhythms are the pattern of physical, mental and behavioral changes that follow a roughly 24-hour cycle. They are found in most living things – from tiny microbes to large mammals – and respond primarily to changes in light and dark in the organism’s environment.
Our circadian rhythms are controlled by biological clocks – groups of interacting molecules found in cells throughout the body. The SCN or “master clock” – which sits in the hypothalamus, an area of the brain just above where the optic nerves from the eyes cross – keeps the molecular clocks in synch.
Although the SCN – which contains around 20,000 neurons – was identified 40 years ago, this new study is the first to pinpoint which group of SCN cells controls its underlying timekeeping mechanisms.
Joseph Takahashi, one of the authors of the study and Professor and Chair of the Neuroscience Department at UT Southwestern Medical Center, says:
“We have found that a group of SCN neurons that express a neuropeptide called neuromedin S (NMS) is both necessary and sufficient for the control of circadian rhythms.”
NMS is a neuropeptide – a protein that brain cells use to send signals. Working with specially-bred mice, the team discovered that brain cells that express NMS act as cellular pacemakers.
When they blocked signal transmission in the NMS cells in the mice, the team found it disrupted the timing mechanism of the SCN and affected the biological clocks in the rest of the body.
The researchers also discovered new clues about how light synchronizes the body clock.
The study represents another step in what has been a long journey by Prof. Takahashi and his lab.
In the 1990s, they identified the first gene related to circadian rhythms in mammals – a gene called Clock. Since then, they have shown that disruptions to Clock, and another gene called Bmal1, affect insulin secretion in the pancreas and can lead to diabetes in mice.
More recently, they showed that the 3D structure of the protein complex formed by these two genes is the battery of the biological clock. In a study published in 2012, they revealed the first atomic-level images of the CLOCK:BMAL1 complex.
The new study was funded by the National Institutes of Health (NIH) and the Howard Hughes Medical Institute (HHMI).
Senior author Masashi Yanagisawa, adjunct professor of Molecular Genetics, former HHMI Investigator at UT Southwestern, says which of the neurons in the SCN are responsible for producing circadian rhythms has been an important question in neurobiology, and:
“This study marks a significant advancement in our understanding of the body clock.”
Prof. Yanagisawa, who is now Director of the World Premier International Institute for Integrative Sleep Medicine at the University of Tsukuba in Japan, discovered that another neuropeptide called orexin controls sleep/wakefulness.
He and his colleagues have since identified numerous pathways involved in the control of appetite and blood pressure, plus other neuropeptides that help regulate functions like metabolism, stress and emotions.