This program of research is directed at elucidating the fundamental mechanisms which lead to alterations in the circadian and sleep promoting system with age. Such changes with age contribute to the high prevalence of sleep disorders in the elderly. We propose to address this issue at the most fundamental level and determine the age-related changes in the molecular mechanisms for these processes. Studies will both address changes with age in known processes, as well as address hypotheses to further our understanding of the mechanisms with age in known processes, as well as address hypotheses to further our understanding of the mechanisms involved. We plan studies in both Drosophila and rats. The former are studied since knowledge of the molecular basis of the circadian block is more complete, and there is growing evidence for an analogy of their rest-like period and sleep. Rats are used since the data on the neuronal circuitry are most complete, and we will investigate molecular mechanisms within the framework of the circuitry involved. In Project 1, we plan to study changes in the molecular mechanisms of the circadian clock in Drosophila. Studies will involve both investigating in vitro and in vivo, using new transgenic technology, alterations with age in the circadian rhythm of expression of the period and timeless genes. These studies will also investigate control of the rest period in Drosophila as an analog of sleep. The effect of manipulating the adenosine system pharmacologically on rest/activity will be studied. Adenosine, a sleep promoting molecule will be the major focus of Subprojects 0002 and 0002 which will be conducted in rats. Using unique facilities, we will study the levels of adenosine in key brain regions in young and old rats and address whether adenosine changes with age and/or in relationship to the duration of prior wakefulness. Adenosine levels are controlled by a complex metabolic system. Enzymes and transporters for adenosine could themselves change with age and/or diurnal effects. This will be addressed in these two projects by studying changes in the various components of the adenosine system t a molecular level Subproject 0002 and how changes in these components alter adenosine in the brain regions relevant to sleep (Subproject 0002). Thus, this Program Project is a comprehensive, integrated series of novel studies to address the changes with age in the sleep and circadian system at a fundamental level. The projects are supported by two cores- an Administrative and Rodent Behavioral and Assessment and Biostatistical Core. Common behavioral assessment protocols and biostatistical approaches facilitate a unique approach for this program of research.

National Institute of Health (NIH)
National Institute on Aging (NIA)
Research Program Projects (P01)
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Special Emphasis Panel (ZAG1-PCR-5 (O1))
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Monjan, Andrew A
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University of Pennsylvania
Internal Medicine/Medicine
Schools of Medicine
United States
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Naidoo, Nirinjini; Zhu, Jingxu; Galante, Raymond J et al. (2018) Reduction of the molecular chaperone binding immunoglobulin protein (BiP) accentuates the effect of aging on sleep-wake behavior. Neurobiol Aging 69:10-25
Zimmerman, John E; Chan, May T; Lenz, Olivia T et al. (2017) Glutamate Is a Wake-Active Neurotransmitter in Drosophila melanogaster. Sleep 40:
Anafi, Ron C; Francey, Lauren J; Hogenesch, John B et al. (2017) CYCLOPS reveals human transcriptional rhythms in health and disease. Proc Natl Acad Sci U S A 114:5312-5317
Nikonova, Elena V; Gilliland, Jason DA; Tanis, Keith Q et al. (2017) Transcriptional Profiling of Cholinergic Neurons From Basal Forebrain Identifies Changes in Expression of Genes Between Sleep and Wake. Sleep 40:
Havekes, Robbert; Abel, Ted (2017) The tired hippocampus: the molecular impact of sleep deprivation on hippocampal function. Curr Opin Neurobiol 44:13-19
Morgan, Andrew P; Gatti, Daniel M; Najarian, Maya L et al. (2017) Structural Variation Shapes the Landscape of Recombination in Mouse. Genetics 206:603-619
Gerstner, Jason R; Lenz, Olivia; Vanderheyden, William M et al. (2017) Amyloid-? induces sleep fragmentation that is rescued by fatty acid binding proteins in Drosophila. J Neurosci Res 95:1548-1564
Brown, Marishka K; Strus, Ewa; Naidoo, Nirinjini (2017) Reduced Sleep During Social Isolation Leads to Cellular Stress and Induction of the Unfolded Protein Response. Sleep 40:
Gardner, Benjamin; Strus, Ewa; Meng, Qing Cheng et al. (2016) Sleep Homeostasis and General Anesthesia: Are Fruit Flies Well Rested after Emergence from Propofol? Anesthesiology 124:404-16
Havekes, Robbert; Park, Alan J; Tolentino, Rosa E et al. (2016) Compartmentalized PDE4A5 Signaling Impairs Hippocampal Synaptic Plasticity and Long-Term Memory. J Neurosci 36:8936-46

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