An important feature of the sleep-wake cycle relates to if and how it is coupled to circadian rhythm. This project examines the hypothesis that sleep has a dominant role in entraining circadian behavior and that there are interactions at a genetic level that promote both the expression of sleep and the effects of sleep state on circadian behavior. A working model identifies the potential influences of serotonergic and/or cholinergic afferent input from state-producing mid-brain regions as mechanisms affecting activation of neurons in the suprachiasmatic nucleus (SCN) and subsequent circadian behavior. Protocols are designed to characterize diurnal rhythms in sleep and circadian behavior in two in-bred strains of mice that differ in relevant sleep, circadian, and/or neurobehavioral characteristics. After quantitification of spontaneously occurring patterns of sleep and circadian behavior, each strain will undergo standardized interventions with restriction or induction of paradoxical sleep to identify gene-by-environment effects on sleep and subsequent circadian behavior. Measures will include sleep architecture (sleep onset, sleep stages, sleep duration), and its physiologic correlates (respiratory rate, heart rate, and metabolic rate), with correlation to diurnal body temperature and activity rhythms, as dependent variables in regard to strain and to intervention (analysis of variance). Some but not all measures will differ less within a strain than between strains, indicating a genetic component to a given trait variable. A second set of outcome measures will be a neurohistologic evaluation of how interventions affect the expression of proteins that reflect neuronal activation and neurotransmitter expression in the SCN and mid-brain regions. Differences among strains in afferent projections to SCN nuclei will be studied by anterograde tract tracing and co-localization with neurotransmitter phenotype. A component of the project is to simplify the instrumentation and engineer minimally invasive monitoring of sleep and circadian behavior. Findings will amplify the novel hypothesis that sleep acts as an intrinsic modifier of SCN function and to discover clues to the genetic and environmental foundations for physiologic traits and neuroanatomic structures involved in sleep.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
1R01HL064278-01
Application #
6045641
Study Section
Special Emphasis Panel (ZHL1-CSR-R (S1))
Project Start
1999-09-30
Project End
2003-08-31
Budget Start
1999-09-30
Budget End
2000-08-31
Support Year
1
Fiscal Year
1999
Total Cost
Indirect Cost
Name
Case Western Reserve University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
077758407
City
Cleveland
State
OH
Country
United States
Zip Code
44106
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