Aging leads to a functional deterioration of multiple physiological systems, including those underlying sleep and wakefulness. Older individuals tend to have reduced sleep amounts and changes in sleep composition and distribution, decreased alertness, increased fragmentation, reduced nocturnal sleep and amplitude of delta EEG frequency. Sleep disruptions in the elderly also severely affect the health and well-being of their caregivers to the point that, in pathologies such as Alzheimer's disease, sleep fragmentation is the main cause of institutionalization. The underlying mechanisms of these changes in sleep architecture and efficiency during aging are unknown. In this proposal, we will use optogenetics to interrogate the role of specific neuronal cell types and circuits in the decline of sleep qualit and cognition during aging. Optogenetics is an ideal method to study sleep/wake mechanisms in rodents because pharmacological approaches far exceed the short time scale of sleep/wake cycles (in the order of minutes), and electrical stimulations cannot provide cellular specificity. n particular we propose to determine whether the ability of three neurotransmitters (Hcrt/orexin, norepinephrine and acetylcholine) to facilitate wakefulness is reduced in old mice.
In aim 2, we will determine whether specific features of sleep quality driven by these three transmitters are relevant for the cognitive decline observed during aging. In a third aim we will test whether a young systemic environment is able to improve sleep composition and distribution in an old mouse using plasma transfer and parabiosis experiments. The data obtained from these experiments may lead to selective therapeutic interventions to improve the quality of life of the elderly and their caregivers.

Public Health Relevance

Aging is accompanied by a progressive decline in sleep quality that severely affects the quality of life of many older adults. In this proposal, we will ue state of the art methods to interrogate whether specific neuronal systems affect specific features of the dynamic of sleep to wake transitions and their consequences in cognitive function. We will also test whether the blood of a young animal can improve sleep performance in an older animal.

National Institute of Health (NIH)
National Institute on Aging (NIA)
Research Project (R01)
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Special Emphasis Panel (ZAG1-ZIJ-5 (J3))
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Mackiewicz, Miroslaw
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Stanford University
Schools of Medicine
United States
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Castellano, Joseph M; Palner, Mikael; Li, Shi-Bin et al. (2016) In vivo assessment of behavioral recovery and circulatory exchange in the peritoneal parabiosis model. Sci Rep 6:29015
de Lecea, Luis (2015) Optogenetic control of hypocretin (orexin) neurons and arousal circuits. Curr Top Behav Neurosci 25:367-78
Roh, Jee Hoon; Jiang, Hong; Finn, Mary Beth et al. (2014) Potential role of orexin and sleep modulation in the pathogenesis of Alzheimer's disease. J Exp Med 211:2487-96
Irmak, Simal Ozen; de Lecea, Luis (2014) Basal forebrain cholinergic modulation of sleep transitions. Sleep 37:1941-51