Center for Sleep and Consciousness

Chiara Cirelli, MD, PhD
University of Wisconsin - Madison
School of Medicine
Department of Psychiatry
6001 Research Park Blvd
Madison, WI 53719
Tel: (608) 263 9236
Fax: (608) 265 2953
e-mail: ccirelli@wisc.edu

Chiara Cirelli received her medical degree at the University of Pisa, Italy. She obtained a Ph.D. in Neuroscience at the Scuola Superiore S. Anna, in Pisa, Italy. Her thesis focused on the molecular changes in gene expression occurring in the brain across sleep and wakefulness. From 1994 to 2000 she was a Fellow of The Neurosciences Institute in San Diego, California. She is currently Associate Professor of Psychiatry at the University of Wisconsin, Madison, where she moved in 2001.

The research in Dr. Cirelli’s laboratory aims at understanding the function of sleep and clarifying the functional consequences of sleep loss. Her team uses a combination of different approaches, from genetics in fruit flies to whole-genome expression profiling in invertebrates and mammals, to behavioral and EEG analysis in mice and rats.

The first approach exploits the power of Drosophila genetics to identify genes involved in sleep regulation. It has recently been demonstrated that fruit flies sleep and need sleep in much the same way as mammals do. This finding has opened the way to the genetic dissection of sleep using mutant screening and other powerful tools of genetic manipulation that are available in Drosophila. Over the past 4 years Dr. Cirelli’s team has performed a 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. More than 10,000 mutant lines have been screened, several candidate lines have been identified, and their molecular and genetic characterization is now being performed. The characterization of one of the most extreme short sleeper mutants has just been completed. This study demonstrated that a point mutation in the voltage-sensing module of the potassium channel Shaker abolishes the Shaker current and decreases sleep from 900 to <300min/day. Shaker-like channels are also present in mammals, and their role in mammalian sleep regulation is now being explored using mice and rats.

The second, molecular approach is used to characterize molecular correlates of sleep and wakefulness. Dr. Cirelli has pioneered the use of whole-genome profiling to identify the genes whose expression changes in the brain in sleep relative to wakefulness. Since 1998, she has pursued such genome-wide screenings in fruit flies, rats, hamsters and humans using high-density DNA microarrays. In rats, it was found that hundreds of genes are differentially expressed in the brain during sleep and waking. These genes belong to diverse and often complementary functional categories, suggesting that sleep and wakefulness favor different cellular processes. Waking-related transcripts are involved in energy metabolism, excitatory neurotransmission, transcriptional activation, synaptic potentiation and memory acquisition, and the response to cellular stress. Sleep-related transcripts are involved in brain protein synthesis, synaptic depression, as well as membrane trafficking and maintenance, including cholesterol metabolism, myelin formation, and synaptic vesicle turnover. Recently it was found that molecular correlates of sleep and wakefulness are also present in flies, and that they are often similar to those described in rats. It was also found that a key factor that controls the modulation of gene expression by behavioral state is the activity of the noradrenergic system, which is high during wakefulness and low during sleep. The laboratory is also actively investigating molecular correlates of prolonged sleep deprivation. Dr. Cirelli and her team have found that sustained sleep loss induces the expression of several antibodies, including autoantibodies, and glial genes. They are now studying whether continuous wakefulness may be detrimental to glial functions. They are also performing a systematic transcriptomic analysis in the brain of patients who died of fatal familial insomnia, to determine whether transcripts coding for autoantibodies and glial proteins are also specifically induced by prolonged sleep loss in humans. The laboratory has just acquired the capability to perform large-scale proteomic profiling in flies, rats, and sparrows. The goal of this project is to identify brain proteins specifically affected by sleep loss.

SOME SIGNIFICANT PAPERS

1. Vyazovskiy VV, Cirelli C, Pfister-Genskow M, Faraguna U, Tononi G. Molecular and electrophysiological evidence for net synaptic potentiation in wake and depression in sleep. Nature Neuroscience, 11:200-8, 2008.

2. Faraguna U, Vyazovskiy VV, Nelson AB, Tononi G, Cirelli C. A causal role for brain-derived neurotrophic factor in the homeostatic regulation of sleep. J Neuroscience, 28:4088-95, 2008.

3. Bushey D, Huber R, Tononi G, Cirelli C. Drosophila Hyperkinetic mutants have reduced sleep and impaired memory. J Neuroscience, 27:5384-93, 2007.

4. Huber R, Tononi G, Cirelli C. Exploratory behavior, cortical BDNF expression and sleep homeostasis. Sleep, 30: 129-139, 2007.

5. Cirelli C. A molecular window on sleep: Changes in gene expression between sleep and wakefulness. The Neuroscientist, 11: 63-74, 2005.

6. Cirelli C, Bushey D, Hill S, Huber R, Kreber R, Ganetzky B, Tononi G. Reduced sleep in Drosophila Shaker mutants. Nature, 434: 1087-1092, 2005.

7. Cirelli C, Lavaute TM, Tononi G. Sleep and wakefulness modulate gene expression in Drosophila. J of Neurochemistry, 94:1411-1419, 2005.

8. Cirelli C, Gutierrez CM, Tononi G. Extensive and divergent effects of sleep and wakefulness on brain gene expression. Neuron 41: 35-43, 2004.

9 Huber R, Hill S, Holladay C, Biesiadecki M, Tononi G, Cirelli C. Sleep homeostasis in Drosophila melanogaster. Sleep 27: 628-639, 2004.

10. Cirelli C. Searching for sleep mutants of Drosophila melanogaster. Bioessays 25: 940-949, 2003.