Sleep and Circadian Rhythms
Many of the individual laboratories in our department work on various aspects of sleep and circadian rhythms, from very basic work in animals to human clinical studies. These include laboratories run by Drs.
Chamberlin, Fuller, Arrigoni, Lu and Mullington.
The basic science components
of this program use a combination of cutting edge genetic and systems neuroscience techniques to dissect the circuitry within the brain that regulates wake-sleep cycles and circadian rhythms. Some of our areas of interest include:
Basic sleep circuitry.
Our laboratories have pioneered the development of a flip-flop model to explain many of the observed phenomena seen in switching from wakefulness to NREM sleep and between NREM and REM sleep. Current studies involve the use of conditional genetic constructs and viral vectors to allow us to manipulate the genes for neurotransmitters and receptors in these circuits. Other experiments use optogenetics or artificial ligand-gated ion channels to turn genetically defined populations of neurons on or off to examine their role in wake-sleep regulation. (Saper, Lu, Arrigoni, Fuller, Scammell)
People with narcolepsy have chronic sleepiness, and episodes of muscular weakness or paralysis known as cataplexy, due to loss of orexin (or hypocretin) neurons in the lateral hypothalamus that produce narcolepsy. We are using conditional knockin mice for the orexin receptors to study the brain pathways that produce the different components of narcolepsy in mice. In addition, we are studying the brains of people with narcolepsy and investigating whether people with narcolepsy have abnormalities in appetite or metabolism. (Scammell, Saper)
The suprachiasmatic nucleus (SCN) in the hypothalamus imposes a 24 hour rhythm on nearly all biological functions, including wake-sleep, feeding, body temperature, and locomotor activity. We explore the brain circuitry by which the SCN imposes that influence. To do this, we use viral vectors in genetically engineered mice to manipulate clock genes as well as genes for neurotransmitters or receptors involved in these circuits, and measure circadian rhythms of a variety of physiological processes. (Saper, Fuller)
Sleep and breathing.
Many people develop obstructive sleep apnea, a condition in which they stop breathing periodically when asleep, due to collapse of their airway. We use transgenic mice to manipulate the neurons involved in regulation of breathing and arousal responses to hypoxia/hypercarbia, to study the brain circuits that regulate airway patency, respiratory drive, and the behavioral and cardiovascular consequences of repeated arousals during sleep. (Chamberlin, Saper)
The clinical components
of this work target both the basic science of sleep-wake control and the effects of sleep loss on pain perception and inflammation.
Human sleep circuitry and genetics.
We receive the brains from subjects in a longitudinal study of elderly individuals, whose wake-sleep behavior was characterized by actigraphic recording of activity. We then examine those brains for the integrity of the wake-sleep and circadian circuitry. These subjects also donate their DNA for study, and all have been genotyped using a 900K SNP chip, thus allowing rapid screening of genotypes that produce specific wake-sleep or circadian phenotypes. (Saper)
Effects of sleep and circadian rhythms on metabolism, inflammation, pain, and cardiovascular response.
We study human subjects who undergo sleep or circadian manipulation, and examine the effects of such disruptions on response to inflammation, glucose metabolism, response to painful stimuli, and vascular reactivity. (Mullington)
Sleep Disorder Treatment