Neuroscientists pinpoint cell type in the brain that controls body clock

Could lead to treatments for jet lag, neurological problems, and metabolism issues, but one simple solution is to not use electronic devices before sleep
March 24, 2015

Suprachiasmatic nucleus controls sleep-wake cycles (credit: National Institute of General Medical Sciences)

UT Southwestern Medical Center neuroscientists have identified key cells in the brain that control 24-hour circadian rhythms (sleep and wake cycles) as well as functions such as hormone production, metabolism, and blood pressure.

The discovery may lead to future treatments for jet lag and other sleep disorders and even for neurological problems such as Alzheimer’s disease, as well as metabolism issues and psychiatric disorders such as depression.

It’s been known since 2001 that circadian rhythms are generated within a specific area of the brain called the suprachiasmatic nucleus (SCN), a tiny region located in the hypothalamus. But that region contains about 20,000 neurons that secrete more than 100 identified neurotransmitters, neuropeptides, cytokines, and growth factors, so researchers have not been able to pinpoint which neurons control circadian rhythms.

Neuromedin S: master controller of circadian rhythms

Now UT Southwestern neuroscientists report in the journal Neuron that they have found “a group of SCN neurons that express a neuropeptide called neuromedin S (NMS) is both necessary and sufficient for the control of circadian rhythms,” according to Dr. Joseph Takahashi*, Chairman of Neuroscience and Howard Hughes Medical Institute (HHMI) Investigator at UT Southwestern, who holds the Loyd B. Sands Distinguished Chair in Neuroscience.

NMS is a neuropeptide — a protein made of amino acids that neurons use to communicate. The researchers found in a mouse study that modulating the internal clock in just the NMS neurons altered the circadian period throughout the whole animal. The study also provided new insights into the mechanisms by which light synchronizes body clock rhythms.

“This study marks a significant advancement in our understanding of the body clock” said senior author Dr. Masashi Yanagisawa**, Adjunct Professor of Molecular Genetics, former HHMI Investigator at UT Southwestern, and current Director of the World Premier International Institute for Integrative Sleep Medicine at the University of Tsukuba in Japan.

The research was supported by the National Institute of Health and the Howard Hughes Medical Institute.

Overexposure to artificial light: don’t use TV, iPads and e-readers before sleeping

Before electricity, sleep occurred in the dark in two phases over 12 hours; in the modern world, sleep is compacted to a short 7 or 8 hour period of dimness encapsulated by electric light (credit: Richard G. Stevens , Yong Zhu/Philosophical Transactions B)

So what’s causing these neuropeptide changes? Scientists have found that modern life — a cycle of inadequate exposure to natural light during the day and overexposure to artificial light at night — can mess with the body’s natural sleep pattern.

The solution may be to change our lighting, says University of Connecticut Health cancer epidemiologist Richard Stevens, who has been studying the effects of artificial lighting on human health for three decades.

“It’s become clear that typical lighting is affecting our physiology,” Stevens says. “We’re learning that better lighting can reduce these physiological effects.

“By that we mean dimmer and longer wavelengths [yellow, orange, red] in the evening, and avoiding the bright blue of e-readers, tablets, and smart phones.”

Stevens and co-author Yong Zhu from Yale University explain this in an open-access paper published in the British journal Philosophical Transactions of the Royal Society B.

The paper summarizes what we know up to now on the effect of lighting on our health, Stevens says. While short-term effects can be seen in [disrupted] sleep patterns, “there’s growing evidence that the long-term implications of this have ties to obesity, diabetes, depression, breast cancer, and possibly other cancers.”

The major culprit is electronic devices, which emit enough blue light when used in the evening to suppress the sleep-inducing hormone melatonin and disrupt the body’s circadian rhythm.

(Blue light wakes us up in the morning, and reddish light, such as in a sunset, puts us to sleep.)

A recent study comparing people who used e-readers to those who read old-fashioned books in the evening showed a clear difference: those using e-readers showed delayed melatonin onset, Stevens said.

“It’s about how much light you’re getting in the evening,” Stevens says. “It doesn’t mean you have to turn all the lights off at eight o’clock every night, it just means if you have a choice between an e-reader and a book, the book is less disruptive to your body clock. At night, the better, more circadian-friendly light is dimmer and … redder, like an incandescent bulb.”

Stevens was on the scientific panel whose work led to the classification of shift work as a “probable carcinogen” by the International Agency on Cancer Research in 2007.

* Takahashi previously identified and cloned the first mammalian gene — called Clock—related to circadian rhythms. Since then, the Takahashi lab has determined that disruptions in the Clock and Bmal1 genes in mice can alter the release of insulin by the pancreas, resulting in diabetes, and they determined the 3-D structure of the CLOCK-BMAL1 protein complex, which are considered to be the batteries of the biological clock.

** Yanagisawa first identified the important role that endothelin plays on the cardiovascular system, and later, with his discovery of orexin, showed that sleep/wakefulness is controlled by a single neuropeptide. His lab has since identified numerous receptors involved in the regulation of appetite and blood pressure, as well as other neuropeptides that play an important role in the regulation of energy metabolism, stress responses, emotions, and other functions.

Abstract of Neuromedin S-Producing Neurons Act as Essential Pacemakers in the Suprachiasmatic Nucleus to Couple Clock Neurons and Dictate Circadian Rhythms

Circadian behavior in mammals is orchestrated by neurons within the suprachiasmatic nucleus (SCN), yet the neuronal population necessary for the generation of timekeeping remains unknown. We show that a subset of SCN neurons expressing the neuropeptide neuromedin S (NMS) plays an essential role in the generation of daily rhythms in behavior. We demonstrate that lengthening period within Nms neurons is sufficient to lengthen period of the SCN and behavioral circadian rhythms. Conversely, mice without a functional molecular clock within Nms neurons lack synchronous molecular oscillations and coherent behavioral daily rhythms. Interestingly, we found that mice lacking Nms and its closely related paralog, Nmu, do not lose in vivo circadian rhythms. However, blocking vesicular transmission from Nms neurons with intact cell-autonomous clocks disrupts the timing mechanisms of the SCN, revealing that Nms neurons define a subpopulation of pacemakers that control SCN network synchrony and in vivo circadian rhythms through intercellular synaptic transmission.

Abstract of Electric light, particularly at night, disrupts human circadian rhythmicity: Is that a problem?

Over the past 3 billion years, an endogenous circadian rhythmicity has developed in almost all life forms in which daily oscillations in physiology occur. This allows for anticipation of sunrise and sunset. This physiological rhythmicity is kept at precisely 24 h by the daily cycle of sunlight and dark. However, since the introduction of electric lighting, there has been inadequate light during the day inside buildings for a robust resetting of the human endogenous circadian rhythmicity, and too much light at night for a true dark to be detected; this results in circadian disruption and alters sleep/wake cycle, core body temperature, hormone regulation and release, and patterns of gene expression throughout the body. The question is the extent to which circadian disruption compromises human health, and can account for a portion of the modern pandemics of breast and prostate cancers, obesity, diabetes and depression. As societies modernize (i.e. electrify) these conditions increase in prevalence. There are a number of promising leads on putative mechanisms, and epidemiological findings supporting an aetiologic role for electric lighting in disease causation. These include melatonin suppression, circadian gene expression, and connection of circadian rhythmicity to metabolism in part affected by haem iron intake and distribution.