Sleep serves a number of functions, including memory storage and synaptic plasticity. One of the most prevalent complaints in the elderly is the dysregulation of sleep/wake patterns and daytime sleepiness. The goal of our research is to define how sleep is altered with age and to identify the molecular mechanisms underlying age-related deterioration of sleep/wake. Because aging is accompanied by alterations in both sleep and memory, defining the role of sleep may help us understand the behavioral, cellular and molecular changes that occur during aging and enable us to identify therapeutic approaches that might reverse these alterations. Aging is associated with increased sleep fragmentation, and the inability to sustain sleep/wake states. What are the underlying mechanisms of these disruptions? What are the consequences of these changes? How do these changes affect the function of sleep? The experiments in this project focus on the molecular and cellular mechanisms responsible for the dysregulation of sleep/wake in aged mice. Our work reveals that the CREB signaling pathway is required to promote and sustain wakefulness. Our proposed research begins by mapping where CREB is required to sustain wakefulness in the brain across the lifespan of mice (Specific Aim 1). We then examine where CREB signaling is reduced in aged animals and how these changes affect gene expression (Specific Aim 2).
In Specific Aim 3, we attempt to rescue age- related fragmentation of sleep/wake by increasing CREB signaling in the brain. Together, the proposed experiments will define how sleep/wake patterns are altered by aging and will identify the molecular and cellular mechanisms underlying these age-related alterations in sleep/wake.

Public Health Relevance

Aging is accompanied by the fragmentation of sleep/wake states and daytime sleepiness. We seek to understand the molecular basis of these age-related changes in sleep to enable us to develop therapeutic approaches to treat the sleep alterations that occur with aging.

National Institute of Health (NIH)
National Institute on Aging (NIA)
Research Program Projects (P01)
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Special Emphasis Panel (ZAG1-ZIJ-5)
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University of Pennsylvania
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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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