While the function of sleep remains a mystery, many of the most successful theories on sleep function, including synaptic downscaling, memory consolidation, developmental maturation, and even many theories on sleep restoration require that sleep must substantially influence aspects of brain plasticity. We demonstrate that increasing sleep restores brain functions supporting short-term memory in each of 12 classic memory mutants without specifically rescuing the causal molecular lesion or structural defect. We also demonstrate that sleep can rescue brain functions supporting long-term memory as assessed by courtship conditioning. Elucidating the underlying molecular mechanisms may shed new light on processes related to sleep function and may ultimately provide a roadmap for using sleep as a therapeutic to slow or reverse cognitive decline associated with degenerative disease and perhaps developmental disorders. Thus, in this proposal we will: 1) identify the circuits that are required to support sleep-dependent changes in adaptive behavior, 2) manipulate specific genes to determine if they are required for sleep induced restoration of memory, and 3) Determine whether the therapeutic role of sleep extends to disorders in which species of toxic proteins can actively impair neuronal functions and/or kill neurons.

Public Health Relevance

We have shown that sleep can restore plasticity to a large collection of well characterized mutants including in a Drosophila model of Alzheimer's disease. We propose to determine how sleep can benefit the brain so as to provide insights into how sleep might be used to slow or reverse cognitive decline associated with degenerative disease, psychiatric disorders.

Agency
National Institute of Health (NIH)
Type
Research Project (R01)
Project #
2R01NS051305-10
Application #
8761646
Study Section
Molecular Neurogenetics Study Section (MNG)
Program Officer
He, Janet
Project Start
Project End
Budget Start
Budget End
Support Year
10
Fiscal Year
2014
Total Cost
Indirect Cost
Name
Washington University
Department
Neurosciences
Type
Schools of Medicine
DUNS #
City
Saint Louis
State
MO
Country
United States
Zip Code
63130
Dissel, Stephane; Angadi, Veena; Kirszenblat, Leonie et al. (2015) Sleep restores behavioral plasticity to Drosophila mutants. Curr Biol 25:1270-81
Dissel, Stephane; Melnattur, Krishna; Shaw, Paul J (2015) Sleep, Performance, and Memory in Flies. Curr Sleep Med Rep 1:47-54
Thimgan, Matthew S; Seugnet, Laurent; Turk, John et al. (2015) Identification of genes associated with resilience/vulnerability to sleep deprivation and starvation in Drosophila. Sleep 38:801-14
Thimgan, Matthew S; Toedebusch, Cristina; McLeland, Jennifer et al. (2015) Excessive daytime sleepiness is associated with changes in salivary inflammatory genes transcripts. Mediators Inflamm 2015:539627
Lucey, Brendan P; Leahy, Averi; Rosas, Regine et al. (2015) A new model to study sleep deprivation-induced seizure. Sleep 38:777-85
Faville, R; Kottler, B; Goodhill, G J et al. (2015) How deeply does your mutant sleep? Probing arousal to better understand sleep defects in Drosophila. Sci Rep 5:8454
Dissel, Stephane; Seugnet, Laurent; Thimgan, Matthew S et al. (2015) Differential activation of immune factors in neurons and glia contribute to individual differences in resilience/vulnerability to sleep disruption. Brain Behav Immun 47:75-85
Donlea, Jeffrey M; Ramanan, Narendrakumar; Silverman, Neal et al. (2014) Genetic rescue of functional senescence in synaptic and behavioral plasticity. Sleep 37:1427-37
Thimgan, Matthew S; Gottschalk, Laura; Toedebusch, Cristina et al. (2013) Cross-translational studies in human and Drosophila identify markers of sleep loss. PLoS One 8:e61016
Vanderheyden, William M; Gerstner, Jason R; Tanenhaus, Anne et al. (2013) ERK phosphorylation regulates sleep and plasticity in Drosophila. PLoS One 8:e81554

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