Chiara
Cirelli
Function of Sleep Using Molecular and Genetic Approaches
E-mail: ccirelli@wisc.edu
Research Strengths: Behavior: Cognition and Emotion, Molecular Neuroscience
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
studies.
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.
Website:
http://tononi.psychiatry.wisc.edu/People/ChiaraCirelli.html
Selected Publications:
- 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.
- Cirelli, C. and G. Tononi. 2004. Locus ceruleus control of state-dependent gene expression. J. Neurosci. 24: 5410-5419.
- 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.
- Cirelli, C. 2003. Searching for sleep mutants of Drosophila melanogaster. Bio. Essays 25: 940-949.
- Shaw, P.J., C. Cirelli, R.J. Greenspan, and G. Tononi. 2000. Correlates of sleep and waking in Drosophila melanogaster. Science 287: 1834-1837.
- Cirelli, C. and G. Tononi. 2000. Differential expression of plasticity-related genes in waking and sleep and their regulation by the noradrenergic system. J. Neurosci. 20: 9187-9194.