Function of Sleep Using Molecular and Genetic Approaches
Departemental Phone: (608) 263-0491
All animal species studied so far spend a large portion of
their life asleep, even if doing so is potentially dangerous. The
amount and quality of sleep are tightly regulated - sleep pressure
increases the longer one stays awake, and becomes overwhelming
after prolonged sleep deprivation. Sleep loss leads to cognitive
impairment and, if prolonged for several weeks, to death. Thus,
sleep appears to fulfill some fundamental function, but what this
function may be remains unknown.
Understanding the function of sleep and clarifying the functional consequences of sleep loss are not just issues of theoretical interest: the National Highway Traffic Safety Administration estimates conservatively that each year drowsy driving is responsible for at least
100,000 automobile crashes, 71,000 injuries, and 1,550 fatalities (National Sleep Foundation, 2002). Current pharmacological attempts at reducing the need for sleep or at making sleep more restorative are hampered by the lack of knowledge of its basic mechanisms and functions. Specifically, the identification of new targets for drug development requires a mechanistic understanding of how sleep is regulated at the cellular level.
My research is aimed at investigating the fundamental mechanisms of sleep by using a combination of molecular and genetic approaches. The molecular approach consists in whole-genome profiling studies to identify all the genes whose expression changes in the brain in sleep
relative to spontaneous wakefulness and sleep deprivation. For the past several years, we have pursued such genome-wide screening mainly in rats, fruit flies, hamsters and, most recently, humans. Our laboratory has recently been able to identify genes that are specifically activated
in the brain of a sleeping animal. These new results suggest that sleep may be especially important for internal membrane trafficking in neural and glial cells. These findings prompt new hypotheses about the functions of sleep that need to be examined through follow-up functional
A second, complementary approach to the functions of sleep exploits the power of Drosophila genetics. Over the past 4 years, we have demonstrated that fruit flies sleep and need sleep in much the same way as we and other mammals do. This finding has opened the way to the genetic dissection of sleep using mutant screening and other powerful tools for genetic manipulation that are available in Drosophila. We have set up a laboratory to perform large-scale mutagenesis screening for sleep phenotypes in Drosophila. The goal is to identify flies that need little sleep as well as flies that are resistant to sleep deprivation. Over the last 2 years, we have screened more than 8000 mutant lines, each carrying a mutation in one single gene, and identified ~ 10 candidate lines that either sleep very little or are resistant to sleep deprivation. We are now performing the necessary molecular and genetic characterization of such mutant lines. The final goal is to identify the cellular mechanisms that allow these mutant flies to be continuously awake and perform well while requiring little or no sleep.
- Bushey D, Hughes KA, Tononi G, Cirelli C (2010) Sleep, aging, and lifespan in Drosophila. BMC Neuroscience, 11: 56.
- Nelson AB, Faraguna U, Tononi G, Cirelli C (2010) Effects of anesthesia on the response to sleep deprivation. Sleep 33: 1659-67.
- Gilestro G, Tononi G, Cirelli C (2009) Widespread changes in synaptic markers as a function of sleep and wakefulness in Drosophila. Science, 324: 109-112.
- Bushey D, Tononi G, Cirelli C (2009) The Drosophila Fragile X mental retardation gene regulates sleep need. J. Neurosci, 29: 1948-1961.
- Cirelli C (2009) The genetic and molecular regulation of sleep: from fruit flies to humans. Nature Reviews Neuroscience, 10: 549-560.
- Hanlon EC, Faraguna U, Vyazovskiy VV, Tononi G, Cirelli C (2009) Effects of skilled training on sleep slow wave activity and cortical gene expression in the rat. Sleep, 32: 719-729.
- Cirelli C, Tononi G. (2008) Is sleep essential? Plos Biology 6:e216.
- Faraguna U, Vyazovskiy VV, Nelson AB, Tononi G, and Cirelli C (2008) A causal role for BDNF in the homeostatic regulation of sleep. J. Neurosci, 28: 4088-4095.
- Bushey D, Huber R, Tononi G, Cirelli C (2007) Drosophila Hyperkinetic mutants have reduced sleep and impaired memory. J. Neurosci, 27: 5384-5393.
- Cirelli, C., R. Huber, A. Gopalakrishnan, T. Southard, and G. Tononi. 2005. Locus Ceruleus control of slow wave homeostasis. J. Neurosci. 25: 4503- 4511.
- Cirelli, C., T.M. Lavaute, G. Tononi. 2005. Sleep and wakefulness modulate gene expression in Drosophila. J. Neurochem. 94: 1411-1419.
- Cirelli, C., D. Bushey, S. Hill, R. Huber, R. Kreber, B. Ganetzky, and G. Tononi. 2005. Reduced sleep in Drosophila Shaker mutants. Nature 434: 1087-1092.
- Cirelli, C. and G. Tononi. 2004. Locus ceruleus control of state-dependent gene expression. J. Neurosci. 24: 5410-5419.
- Huber, R., S. Hill, C. Holladay, M. Biesiadecki, G. Tononi, and C. Cirelli. 2004. Sleep homeostasis in Drosophila melanogaster. Sleep 27: 628-639.
- Cirelli, C., C.M. Gutierrez, and G. Tononi. 2004. Extensive and divergent effects of sleep and wakefulness on brain gene expression. Neuron 41: 35-43.
- Gopalakrishnan, A., L.L. Ji, and C. Cirelli. 2004. Oxidative stress and cellular damage after sleep deprivation. Sleep 27: 27-34.