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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 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. We and others have demonstrated in 2000 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 12 years we have screened more than 15,000 mutant lines (> 200,000 individual flies) and identified several candidate lines, including in 2005 the first characterization of an extreme short sleeper mutant carrying a mutation in Shaker, a voltage-dependent potassium channel. Several mutations that modify daily sleep amounts affect genes involved in synaptic plasticity, including the Drosophila homologue of the gene coding for the fragile X metal retardation protein. Overall, it appears that sleep need is related to synaptic plasticity, an idea that we are actively testing in several animal models, and with different approaches.

The second approach involves whole-genome profiling using high-density DNA microarrays to identify the genes whose expression changes in the brain in sleep relative to wakefulness. In rats, for instance, we found that hundreds of genes are differentially expressed in the brain during sleep and wake. These genes belong to diverse and often complementary functional categories, suggesting that sleep and wake favor different cellular processes. Wake-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. We 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 wake and low during sleep. High noradrenaline levels during wake are required for the induction of transcripts involved in synaptic plasticity and in the cellular response to stress. By contrast, low noradrenaline levels during sleep are associated with the increased expression of transcripts favoring protein synthesis. We are currently using transgenic lines that allow us to isolate sleep-related and waking-related transcripts in specific brain cell populations, i.e. neurons, astrocytes, and oligodendrocytes separately. The work is in progress, but we have already isolated hundreds of oligodendrocytic and astrocytic mRNAs that are modulated by sleep or sleep loss.

The results of these and other studies have prompted a new hypothesis about the functions of sleep. Specifically, Dr. Giulio Tononi and I have hypothesized that the amount of synaptic potentiation that occurs during waking is a major determinant of sleep intensity, and that sleep is needed to down-regulate synaptic weight. The synaptic homeostasis hypothesis is being tested at several different levels in a joint effort, ranging from computer simulations and high-density EEG and transcranial magnetic stimulation experiments in humans to molecular, behavioral, and electrophysiological experiments in flies and rodents. Over the past several years we confirmed in several studies in adult flies, rats and humans that learning, enriched experience, and the occurrence of synaptic potentiation during wake increase sleep need and sleep intensity. We also found that in adult flies, protein levels of key components of central synapses, as well as synapse number, are high after waking and low after sleep in all major areas of the Drosophila brain. Similarly, in adult rats, we found that established molecular and/or electrophysiological markers of synaptic strength are high after wake and low after sleep in cortex and hippocampus. Moreover, in adolescent mice, sleep favors spine pruning, while wake favors spine growth. Overall, these data suggest that wake is associated with net synaptic potentiation, whereas sleep may favor global synaptic depression, thereby helping to preserve an overall balance of synaptic strength. Our current experiments in transgenic flies and mice use confocal and repeated in vivo two-photon microscopy, as well as electron microscopy, to determine whether an essential function of sleep is to promote a homeostatic reduction in synaptic strength. We are also testing whether lack of sleep, especially during adolescence, may have long-term consequences for the functional and anatomical connectivity of the brain.

SOME SIGNIFICANT PAPERS

1. Bushey D, Tononi G, Cirelli C. Sleep and synaptic homeostasis: structural evidence in Drosophila. Science, 332(6037):1576-1581, 2011.

2. Maret S, Faraguna U, Nelson AB, Cirelli C, Tononi G. Sleep and wake modulate spine turnover in the adolescent mouse cortex. Nat Neurosci., 14(11):1418-20, 2011.

3. Gilestro GF, Tononi G, Cirelli C. Widespread changes in synaptic markers as a function of sleep and wakefulness in Drosophila. Science, 324:109-12, 2009.

4. 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.

5. 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.

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

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

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

9. 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.

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

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

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

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

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