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Important new discoveries in neurobiology of sleep

June 1, 2006

Two important papers from the Systems Neurobiology Group laboratory of Harvard Medical School Division of Sleep Medicine faculty member Clifford B. Saper, PhD:

Authors Jun Lu, David Sherman, Marshall Devor and Clifford B Saper published a lead Article, "A putative flip-flop switch for control of REM sleep", in the journal Nature in June 2006, describing for the first time a model for how the brain controls REM sleep. 

Authors Joshua J. Gooley, Ashley Shomer and Clifford B. Saper published an important article, "The dorsomedial hypothalamic nucleus is critical for the expression of food-entrainable circadian rhythms", in Nature Neuroscience in March 2006 describing for the first time the role of the dorsomedial nucleus of the hypothalamus in providing a timing signal that can drive circadian rhythms based upon food availability.

Related Links:
Commentary by Clifford B. Saper, PhD
Nature: A putative flip-flop switch for control of REM sleep
Nature Neuroscience: The dorsomedial hypothalamic nucleus is critical for the expression of food-entrainable circadian rhythms
Boeve BF, Saper CB. REM sleep behavior disorder: a possible early marker for synucleinopathies.
Neurology. 2006 Mar 28;66(6):796-7. PMID: 16567693

An editorial by Clifford B. Saper of Harvard Medical School, and Brad Boeve of the Mayo Clinic, reviewing several new papers that indicate that REM behavior disorders may be the earliest sign of some movement disorders, such as Parkinson’s disease.

Commentary by Dr. Clifford B. Saper:
Humans spend about one-third of our lives asleep.  These wake-sleep cycles shape our existence, and those who have trouble sleeping know that violating them can leave you feeling miserable, impair your intellectual performance the next day, and even result in a much higher incidence of drowsy-driving automobile accidents and fatalities.  Over the last few years, we have learned a great deal about the brain circuitry that shapes our wake-sleep cycles, and fits them into the overall daily (circadian) pattern of life.

Sleep is governed by a series of flip-flop switches, which are specialized brain circuits that are designed to produce sharp transitions between different wake-sleep states.  A flip-flop switch has two halves, which inhibit each other.  Wakefulness is driven by a network of nerve cells in the upper part of the lower part of the brain, the brainstem and basal forebrain, which keep the upper part of the brain, the thalamus and cerebral cortex awake.  These nerve cells are turned off by a switch in the hypothalamus, a part of the brain that sits just behind the eyes.  The switch, called the ventrolateral preoptic nucleus, is also inhibited by the arousal system.  This mutual inhibition insures that when either side gains the upper hand, it promptly turns the other side off, causing one to “fall asleep” or to “pop awake” suddenly.

Within sleep, the brain varies between a state when the brain slows down as the arousal systems turn off, and a very different state, associated with active dreaming, when the brainwaves become fast, the body becomes paralyzed so it cannot act out the dreams, and there are rapid eye movements (REM sleep).  REM sleep is controlled by another flip-flop switch in the upper part of the brainstem.  This switch can ordinarily only be flipped when the first (wake-sleep) switch is in the sleep mode.  However, in people with narcolepsy, this switch is not regulated properly, and dream states and episodes of paralysis may occur during wakefulness. 

Finally, the brain has a biological clock, the suprachiasmatic nucleus, that maintains a 24 hour rhythm of activities, even if we are locked away in a cave with no time clues.  This clock can be reset by light cycles, or by a variety of behavioral cues such as food availability.  In addition, this clock can drive daytime wakefulness as it does in humans and other diurnal animals, or nighttime wakefulness as it does in bats and other nocturnal animals.  But the suprachiasmatic nucleus itself is locked to the light-dark rhythm, always being maximally active during the light cycle (or presumed light cycle if one is in constant darkness).  How does the brain maintain nocturnal vs. diurnal animals, and how does it adjust to behavioral cues?  The answer turns out to be a series of relays from the suprachiasmatic nucleus, which ultimately contact the wake-sleep circuitry.  However, the two relays between the suprachiasmatic nucleus and the wake-sleep system are more flexible.  They can be reset by behavioral circumstances, such as food availability, and can even override the suprachiasmatic nucleus entirely if necessary.

As a result of these new insights, we are now able to look for new drugs that can help us control the wake-sleep cycle more effectively.  These will include both new drugs that can help the brain remain awake during the day, as well as drugs that can help us to activate the intrinsic sleep circuitry of the brain more effectively, to induce sleep.

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