The aging process involves progressive deterioration of many physiological functions over time. Sleep which serves a restorative function is also disrupted with aging. There is fragmentation of both sleep and wake and daytime sleepiness is a common problem in the elderly. Increased daytime sleepiness may be a consequence of poor nighttime sleep quality or an impaired ability to maintain wakefulness. Fragmentation of wake occurs largely as a result of an inability to sustain long bouts of wakefulness. The mechanisms for this change and its consequences are unknown. We have found that Homerl scaffolding proteins that are found in the post-synaptic density modulate the stability of sustaining state. Mice lacking the dominant negative short form of Homerl, Homeria, are unable to maintain wakefulness during the active period much like the aged. We hypothesize that the maintenance of wake requires Homeria and that declines in or loss of this mechanism leads to behavioral state instability that is observed during aging. This proposal will seek to determine the molecular mechanisms by which Homeria contributes to the maintenance of wake and how these change with age to understand the molecular basis of wake fragmentation with age. Our proposed studies will determine the cellular basis of Homerl a-dependent control of sustained wake by mapping where in the brain Homeria is required (Specific Aim1). Using metabotropic glutamate receptor (mGluR) transgenic knockin mice we will explore a novel signaling pathway to determine the mechanism underlying Homeria action in the maintenance of wakefulness (Specific Aim 2).
In Specific Aim 3 we will examine where in the brain Homeria is reduced with aging, investigate age-related molecular changes in the Homerla-mGluR signaling pathway and finally determine how declining Homeria expression that occurs with aging correlates with the inability to maintain wakefulness.

Public Health Relevance

Fragmentation of sleep and wake occur with aging. This results from an inability to maintain behavioral state. Our studies seek to understand the molecular mechanisms underlying the maintenance of sleep and wake states and determine how they change with age.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Research Program Projects (P01)
Project #
2P01AG017628-11
Application #
8516247
Study Section
Special Emphasis Panel (ZAG1-ZIJ-5 (J2))
Project Start
Project End
Budget Start
2013-04-01
Budget End
2014-03-31
Support Year
11
Fiscal Year
2013
Total Cost
$269,845
Indirect Cost
$101,192
Name
University of Pennsylvania
Department
Type
DUNS #
042250712
City
Philadelphia
State
PA
Country
United States
Zip Code
19104
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
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
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
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
Havekes, Robbert; Park, Alan J; Tudor, Jennifer C et al. (2016) Sleep deprivation causes memory deficits by negatively impacting neuronal connectivity in hippocampal area CA1. Elife 5:
Tudor, Jennifer C; Davis, Emily J; Peixoto, Lucia et al. (2016) Sleep deprivation impairs memory by attenuating mTORC1-dependent protein synthesis. Sci Signal 9:ra41
Perron, Isaac J; Pack, Allan I; Veasey, Sigrid (2015) Diet/Energy Balance Affect Sleep and Wakefulness Independent of Body Weight. Sleep 38:1893-903

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