Abnormalities in muscle tone control across the sleep cycle lead to grave health problems. Sleep apnea causes hypertension, hypoxic necrosis, cognitive difficulties, heart failure and stroke. Sleepwalking often results in serious injury. Periodic limb movements during sleep (PLMS) can cause profound insomnia, particularly when linked to the restless leg syndrome (RLS). Nocturnal bruxism produces severe dental problems. Sleep apnea occurs in both nonREM and REM sleep. Sleepwalking, PLMS and nocturnal bruxism occur predominantly in nonREM sleep. Despite the link between these common disorders and nonREM sleep, most of our knowledge of motor control during sleep concerns the mechanisms underlying muscle tone suppression in REM sleep. The focus on REM sleep related aspects of motor disorders can be explained in part by the ease of triggering a REM sleep-like state in decerebrate or anesthetized animals by microinjection of carbachol or other substances. In contrast, nonREM sleep motor control mechanisms can only be investigated in intact, unanesthetized animals. We propose to determine the neurochemistry of muscle tone control in nonREM sleep using in vivo investigations in unrestrained, intact animals. We will also examine motor control in natural REM sleep. We will determine how monoamines, amino acids and acetylcholine are released onto motoneurons across the sleep cycle. We will take advantage of recent advances that we have made in the development of sensitive assays for GABA, hypocretin (Hcrt) and acetylcholine. We will also employ newly developed biosensors that have produced an order of magnitude increase in the temporal resolution of measurements of glutamate levels. We will infuse agonists, antagonists and reuptake blockers through dialysis membranes to determine the effects of these transmitters on muscle tone in nonREM sleep. Recent work has documented extensive neocortical and cerebellar damage in both human sleep apnea and animal models of sleep apnea. Initial damage in these areas appears to be a precipitating cause of sleep apnea in a large proportion of patients. Greater damage follows as a consequence of apnea. We will determine the effects of similar damage in rats on neurotransmitter release onto motoneurons in both nonREM and REM sleep. This will improve our understanding of this process, and lay the foundation for pharmacological intervention to interrupt the positive feedback loop that sustains and intensifies the sleep apnea syndrome. Our work will also suggest improved pharmacological treatments for PLMS, sleepwalking and bruxism.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL041370-19
Application #
7667736
Study Section
Biological Rhythms and Sleep Study Section (BRS)
Program Officer
Twery, Michael
Project Start
1988-08-01
Project End
2010-06-30
Budget Start
2009-07-01
Budget End
2010-06-30
Support Year
19
Fiscal Year
2009
Total Cost
$305,865
Indirect Cost
Name
University of California Los Angeles
Department
Type
Schools of Medicine
DUNS #
092530369
City
Los Angeles
State
CA
Country
United States
Zip Code
90095
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