Sleep in the elderly is generally recognized as being of poorer quality than in younger adults. Nocturnal sleep in seniors is characterized by frequent awakenings, decreases in the quantity of deep slow wave sleep (Stages 3 and 4), and a concomitant decrease in delta frequencies in the EEG. Daytime alertness is reduced and naps are common, indicating diminution of the diurnal rhythms of sleep and wakefulness. Many of these changes in sleep architecture also occur in aged laboratory rodents. Our long-term objective is to understand the neural basis of age-related sleep dysfunction. The hypocretin/orexin (H/O) neurotransmitter system has recently been identified as being important in arousal state regulation, and degeneration of the H/O neurons has been found in human narcolepsy, a sleep disorder characterized by excessive daytime sleepiness and cataplexy. Therefore, this system is an attractive target to study with respect to sleep and aging. The overall hypotheses of this proposal are that (1) the H/0 system is important in the maintenance of wakefulness; (2) a dysfunction of the H/O system occurs in the aged; and (3) this dysfunction is related to the sleep/wake disturbances characteristic of the elderly. Based on the literature, we conclude that aged rodents, like elderly humans, are a heterogenous population and differ with respect to their rate of physiological aging. Therefore, we will identify a subpopulation of aged rats having disrupted body temperature rhythms and sleep architecture and use these animals to test the following specific hypotheses: (1) an age-related decline occurs in the number of H/O cells in aged F344 rats that is correlated with disrupted sleep architecture; (2) an age-related decline occurs in the levels of H/O mRNA and/or peptides; (3) waking-related activation of H/O cells declines with age; (4) the release of H/O peptides decreases with age; (5) an age-related decline in the mRNA for the H/O receptor 1 and receptor 2 occurs in brain regions associated with wakefulness; and (6) an age-related decrease in binding to H/O receptor 1 and receptor 2 and/or G protein activation occurs in arousal-related brain regions. To address these questions, we will use a combination of in vivo physiological, neuroanatomical, molecular, and receptor pharmacological methods.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Research Project (R01)
Project #
5R01AG020584-04
Application #
7006953
Study Section
Special Emphasis Panel (ZRG1-IFCN-1 (03))
Program Officer
Monjan, Andrew A
Project Start
2003-02-15
Project End
2008-01-31
Budget Start
2006-02-01
Budget End
2007-01-31
Support Year
4
Fiscal Year
2006
Total Cost
$470,020
Indirect Cost
Name
Sri International
Department
Type
DUNS #
009232752
City
Menlo Park
State
CA
Country
United States
Zip Code
94025
Morairty, Stephen R; Wisor, Jonathan; Silveira, Kristy et al. (2011) The wake-promoting effects of hypocretin-1 are attenuated in old rats. Neurobiol Aging 32:1514-27
Hara, Junko; Gerashchenko, Dmitry; Wisor, Jonathan P et al. (2009) Thyrotropin-releasing hormone increases behavioral arousal through modulation of hypocretin/orexin neurons. J Neurosci 29:3705-14
Matsuki, Taizo; Nomiyama, Mika; Takahira, Hitomi et al. (2009) Selective loss of GABA(B) receptors in orexin-producing neurons results in disrupted sleep/wakefulness architecture. Proc Natl Acad Sci U S A 106:4459-64
Kilduff, Thomas S; Lein, Ed S; de la Iglesia, Horacio et al. (2008) New developments in sleep research: molecular genetics, gene expression, and systems neurobiology. J Neurosci 28:11814-8
Gerashchenko, Dmitry; Wisor, Jonathan P; Burns, Deirdre et al. (2008) Identification of a population of sleep-active cerebral cortex neurons. Proc Natl Acad Sci U S A 105:10227-32
Xie, Xinmin; Wisor, Jonathan P; Hara, Junko et al. (2008) Hypocretin/orexin and nociceptin/orphanin FQ coordinately regulate analgesia in a mouse model of stress-induced analgesia. J Clin Invest 118:2471-81
Yamanaka, Akihiro; Muraki, Yo; Ichiki, Kanako et al. (2006) Orexin neurons are directly and indirectly regulated by catecholamines in a complex manner. J Neurophysiol 96:284-98
Xie, Xinmin; Crowder, Tara L; Yamanaka, Akihiro et al. (2006) GABA(B) receptor-mediated modulation of hypocretin/orexin neurones in mouse hypothalamus. J Physiol 574:399-414
Tsujino, Natsuko; Yamanaka, Akihiro; Ichiki, Kanako et al. (2005) Cholecystokinin activates orexin/hypocretin neurons through the cholecystokinin A receptor. J Neurosci 25:7459-69
Wisor, Jonathan P; Kilduff, Thomas S (2005) Molecular genetic advances in sleep research and their relevance to sleep medicine. Sleep 28:357-67

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