There are profound changes in sleep and wake in older adults. This is found in all species studied from Drosophila to humans. The major changes are in the ability to sustain state, in particular long bouts of wakefulness. Moreover, the amount of sleep is decreased. In humans, this has adverse consequences that are amplified in the presence of comorbidities. While the phenomena are well known, the mechanisms producing these clinically relevant changes are not. In this program of research we propose a new approach to this question by investigating changes in molecular mechanisms using the mouse as a model system. The overall program addresses alternative hypotheses and uses novel transgenic mice to address our overall question. The first project (T. Abel, PL) addresses the role of the cyclic AMP response element binding protein (CREB) in age-related changes in the ability to sustain wakefulness. The investigators argue that changes in this mechanism across the lifespan affect the ability to sustain wakefulness in older mice. They propose studies to localize the neuronal group responsible for the effect and also to rescue this effect of age on wakefulness by transgenically manipulating this pathway. Project 02 (N. Naidoo, PL) addresses the role of one particular CREB target, i.e.. Homer 1a. Recent data have shown that Homer 1a is essential to sustain long bouts of wakefulness. This project seeks to determine the following: in which neuronal groups this effect is mediated; the mechanism of action based on a specific hypothesis about interaction with mGLuR5; and how the pathway is altered by aging. Project 03 (A. Pack, PL) takes a complementary strategy and focuses on neuronal groups known to be involved in wake/sleep control and stabilization of state, i.e., orexin neurons and galanin cells i the ventrolateral preoptic area. Changes in function of these neurons with age are assessed as is reduction of cell number with aging (neurostereology). A major focus of this project is the ER stress response pathway. The hypothesis is that changes in this pathway lead to the age-related changes in neuronal function and cell number. These three projects are supported by three cores; a) Administrative Core; b) Mouse Behavioral Core; and c) Biostatistics and Bioinformatics Core.

Public Health Relevance

Aging results in changes in wake and sleep behavior. Wakefulness is difficult to sustain and there are reductions in sleep. These changes have adverse consequences. They are amplified in individuals with comorbidities. While these changes have been well characterized, the underlying mechanisms are unknown. We propose a molecular approach using the mouse as a model system. Identifying the relevant pathways involved will provide new targets for interventions.

National Institute of Health (NIH)
National Institute on Aging (NIA)
Research Program Projects (P01)
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Special Emphasis Panel (ZAG1)
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Mackiewicz, Miroslaw
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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
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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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