SRI International Scientists Discover Brain Circuit Activated during Sleep Findings may help explain the mechanics of sleepiness and wakefulness

MENLO PARK, Calif., Dec. 10, 2013 /PRNewswire/ -- Neuroscientists at SRI International have discovered a brain circuit that appears to be related to the restorative function of sleep. The findings point to a biochemical and physiological explanation of how sleep need, which gradually builds up during wakefulness, is dissipated during sleep.

"We all know sleep is important for restoration in some way, but scientists have yet to define what actually needs to be restored or how the restoration occurs," said the study leader, Thomas Kilduff, Ph.D., who directs the Center for Neuroscience within SRI Biosciences. "We have found a group of cells in the cerebral cortex that appear to orchestrate the slow waves that occur during sleep, which have been linked to sleep restoration."

The research, published in the December 10 issue of Proceedings of the National Academy of Sciences (PNAS), identifies specific brain cells that are activated during the deep stages of sleep known as slow wave sleep, and identifies the chemical responsible as nitric oxide. The long-term implications of these findings include nitric oxide as a potential target for medications that help facilitate slow wave sleep in conditions where it is diminished, such as aging.

Sleep researchers have long sought to understand why we become sleepy and how sleep restores mental and physical performance. "One clue to sleepiness is that the recovery process during sleep seems to be related to brain slow wave activity, which is high when we first fall asleep and declines through the night," said Kilduff. "When we stay awake for a longer period of time, once we fall asleep, the slow waves are larger in size and more intense."

Sleep stages are identified by electroencephalography (EEG), which measures the electrical activity that brain cells generate as they relay information through neural circuits. Slow wave sleep is characterized by slow EEG frequencies (between 0.5 and 4.5 Hertz) that distinguish it from rapid eye movement sleep and wakefulness.

During slow wave sleep, cells of the cortex have long been known to be relatively inactive, but in 2008, Kilduff's team published results finding that a small number of specific neurons in the cortex of the brain were activated during sleep. "When we saw this activity in the cortex during slow wave sleep, we thought this might provide a link to help understand sleep restoration," said Kilduff.

In the current study, SRI researchers used two chemical markers—one on the outside of brain cells called NK1 and the other on the inside of the cell called nNOS—to investigate the activity of the sleep-active neurons in more detail. The researchers found that the proportion of nNOS/NK1 cells that are activated is dependent on the duration of wakefulness prior to sleep onset and the intensity of the slow waves during the subsequent sleep period.

The enzyme nNOS produces nitric oxide, which is found in many areas of the brain. When nNOS was eliminated from inside brain cells, slow wave activity could no longer be properly produced and sleep was shorter, of poor quality, and did not reduce sleepiness. Only nNOS cells in the cortex are activated during sleep, implying that it is not the presence of nitric oxide elsewhere in the brain that plays a role in slow wave sleep, but specifically its effect in the cortex.

The researchers conclude that the brain cells they identified are part of a critical brain circuit that responds to the sleep "debt" that builds up during long periods of waking activity. When sleep occurs, these cells activate a pathway that releases nitric oxide, produces slow waves, and results in long, uninterrupted periods of sleep.

The scientists next want to know whether these cells respond to the chemical adenosine, which is known to build up in our brains during wakefulness. They are intrigued by the role of NK1 on the outside of nNOS cells in the cortex, as NK1 is a receptor for a neurotransmitter known as Substance P, a chemical not currently known to be involved in sleep. They also want to know whether nNOS/NK1 neurons are related to the decrease in slow wave activity that occurs in aging, particularly because the decline in slow waves has recently been linked to age-related memory impairment.

In addition to Kilduff, other SRI researchers who participated in this study include Stephen Morairty, Ph.D.; Lars Dittrich, Ph.D.; Ravi Pasumarthi, D.V.M., Ph.D.; Daniel Valladao, B.S.; Jaime Heiss, Ph.D.; and Dmitry Gerashchenko, M.D., Ph.D. (now at Harvard Medical School/VA Medical Center).

The research was supported by Award Number R01HL059658 from the National Heart, Lung, And Blood Institute, USAMRAA Grant DR080789P1, DFG Fellowship DI 1718/1-1, and SRI International internal research funds.

The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Heart, Lung, And Blood Institute or the National Institutes of Health.

The U.S. Army Medical Research Acquisition Activity, 820 Chandler Street, Fort Detrick MD 21702-5014 is the awarding and administering acquisition office of USAMRAA Grant DR080789P1. The content of the information does not necessarily reflect the position or the policy of the Government, and no official endorsement should be inferred.

About SRI's Biosciences Division

SRI Biosciences carries out basic research, drug discovery, and drug development. SRI has all of the resources necessary to take R&D from initial discoveries to clinical trials. SRI's product pipeline has yielded marketed drugs, therapeutics currently in human testing, and additional programs at earlier stages. SRI Biosciences offers a wide range of contract research organization (CRO) services, helping government and industry clients and partners advance drugs and other biomedical products toward commercialization. SRI is also working to create the next generation of technologies in areas such as diagnostics, drug delivery, medical devices, and systems biology.

About SRI International

Innovations from SRI International have created new industries, billions of dollars of marketplace value, and lasting benefits to society—touching our lives every day. SRI, a nonprofit research and development institute based in Silicon Valley, brings its innovations to the marketplace through technology licensing, new products, and spin-off ventures. Government and business clients come to SRI for pioneering R&D and solutions in computing and communications, chemistry and materials, education, energy, health and pharmaceuticals, national defense, robotics, sensing, and more.

Visit SRI's website and Timeline of Innovation to learn more about SRI.

SOURCE SRI International



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