PRINCIPAL INVESTIGATOR
University of Wisconsin-Madison
BIO
Chiara Cirelli received her medical degree and Ph.D. in Neuroscience from the University of Pisa, Italy, where she began her investigation of the molecular correlates of sleep and wakefulness and the role of the noradrenergic system in sleep regulation. She continued this work at the Neuroscience Institute in San Diego, California as a fellow in experimental neuroscience, and subsequently at the University of Wisconsin–Madison, where she has been a Professor in the Department of Psychiatry since 2001.
Dr. Cirelli’s research is aimed at investigating the fundamental mechanisms of sleep regulation by using a combination of molecular and genetic approaches. By performing whole-genome expression profiling studies in different species her laboratory has characterized hundreds of genes whose expression changes in neurons and glial cells in sleep relative to wakefulness. This analysis has identified specific cellular processes that are favored by sleep and impaired by sleep deprivation. In a second, complementary approach Dr. Cirelli’s laboratory has been performing a large-scale mutagenesis screening for sleep phenotypes in Drosophila. Several mutant fly lines that have much reduced sleep or are resistant to sleep deprivation have been found. The characterization of the genes mutated in these lines has identified key cellular pathways involved in the regulatory mechanisms of sleep and its functional consequences. Overall, these molecular and genetic studies have shown that sleep need is strongly related to experience-dependent plasticity during wake.
Together with her long-term collaborator, Dr. Giulio Tononi, Dr. Cirelli has developed a comprehensive hypothesis about the function of sleep, the synaptic homeostasis hypothesis, according to which sleep serves to renormalize synaptic strength, counterbalancing a net increase of synaptic strength due to plasticity during wakefulness. Without sleep, such progressive increase in synaptic strength would lead to unsustainable costs in terms of energy, space and cellular supplies, would reduce the informativeness of neuronal signals, and would prevent further learning by bringing stronger synapses closer to their level of saturation. In short, according to this hypothesis sleep is the price to pay for brain plasticity during wakefulness.
The synaptic homeostasis hypothesis is being tested at different levels, using electrophysiological and behavioral experiments in humans, in vitro studies in cortical slices, electron microscopy experiments in flies and mice, and fMRI and DTI experiments in humans. Overall, these experiments confirm that wake is associated with net synaptic potentiation, whereas sleep favors global synaptic renormalization, thereby helping to preserve an overall balance of synaptic strength. Current experiments in transgenic flies and mice use confocal and repeated in vivo two-photon microscopy and block-face scanning electron microscopy to confirm that an essential function of sleep is to promote a homeostatic reduction in synaptic strength. Other experiments are also testing whether lack of sleep, especially during adolescence, may have long-term consequences for the functional and anatomical connectivity of the brain.
SELECTED PUBLICATIONS
Flores CC, Loschky SS, Marshall W, Spano GM, Massaro Cenere M, Tononi G, Cirelli C (2021) Identification of Ultrastructural Signatures of Sleep and Wake in the Fly Brain. Sleep, 24: 1348-1355. doi: 10.1093/sleep/zsab235
Miyamoto D, Marshall W, Tononi G, Cirelli C (2021) Net decrease in spine-surface GluA1-containing AMPA receptors after post-learning sleep in the adult mouse cortex. Nature Communications, no. 12. doi: 10.1038/s41467-021-23156-2
Cirelli C, Tononi G (2021) The why and how of sleep-dependent synaptic down-selection. Seminars in Cell & Developmental Biology, S1084-9521(21)00031-8. doi: 10.1016/j.semcdb.2021.02.007
Tononi G, Cirelli C (2020) Sleep and synaptic down-selection. European Journal of Neuroscience, 51(1): 413-421. doi: 10.1111/ejn.14335
de Vivo L, Nagai H, De Wispelaere N, Spano GM, Marshall W, Bellesi M, Nemec KM, Schiereck SS, Nagai M, Tononi G, Cirelli C (2019) Evidence for sleep-dependent synaptic renormalization in mouse pups. Sleep, 42(11): 1-14. doi: 10.1093/sleep/zsz184
Honjoh, S., Sasai, S., Schiereck, S., Nagai, H., Tononi, G., & Cirelli, C. (2018). Regulation of cortical activity and arousal by the matrix cells of the ventromedial thalamic nucleus. Nature Communications, 9(1), 2100.
Nir, Y., Andrillon, T., Marmelshtein, A., Suthana, N., Cirelli, C., Tononi, G., & Fried, I. (2017). Selective neuronal lapses precede human cognitive lapses following sleep deprivation. Nat Med, 23, 1474-1480.
Funk, C., Peelman, K., Bellesi, M., Marshall, W., Cirelli, C., & Tononi, G. (2017). Role of Somatostatin-Positive Cortical Interneurons in the Generation of Sleep Slow Waves. The Journal of Neuroscience, 37(38), 9132–9148.
Bellesi, M., Vivo, L., Chini, M., Gilli, F., Tononi, G., & Cirelli, C. (2017). Sleep Loss Promotes Astrocytic Phagocytosis and Microglial Activation in Mouse Cerebral Cortex. J Neurosci, 37(21), 5263–5273.
de Vivo, L., Bellesi, M., Marshall, W., Bushong, E., Ellisman, M., Tononi, G., & Cirelli, C. (2017). Ultrastructural evidence for synaptic scaling across the wake/sleep cycle. Science, 355(6324), 507–510.
Billeh, Y., Rodriguez, A., Bellesi, M., Bernard, A., de Vivo, L., Funk, C., Harris, J., Honjoh, S., Mihalas, S., Ng, L., Koch, C., Cirelli, C., & Tononi, G. (2016). Effects of chronic sleep restriction during early adolescence on the adult pattern of connectivity of mouse secondary motor cortex. eneuro.
Bellesi, M., de Vivo, L., Tononi, G., & Cirelli, C. (2015). Effects of sleep and wake on astrocytes: clues from molecular and ultrastructural studies.BMC biology, 13(1), 66.
Bellesi, M., Tononi, G., Cirelli, C., & Serra, P. (2015). Region-specific dissociation between cortical noradrenaline levels and the sleep/wake cycle. Sleep, 39(1), 143–154.
Bushey, D., Tononi, G., & Cirelli, C. (2015). Sleep-and wake-dependent changes in neuronal activity and reactivity demonstrated in fly neurons using in vivo calcium imaging. Proceedings of the National Academy of Sciences, 112(15), 4785–4790.
Bernardi, G., Siclari, F., Yu, X., Zennig, C., Bellesi, M., Ricciardi, E., Cirelli, C., Ghilardi, M., Pietrini, P., & Tononi, G. (2015). Neural and behavioral correlates of extended training during sleep deprivation in humans: evidence for local, task-specific effects. Journal of Neuroscience, 35(11), 4487–4500.
Cirelli, C., & Tononi, G. (2015). Cortical Development, Electroencephalogram Rhythms, and the Sleep/Wake Cycle. Biological psychiatry, 77(12), 1071–1078.
Nir, Y., Vyazovskiy, V., Cirelli, C., Banks, M., & Tononi, G. (2015). Auditory responses and stimulus-specific adaptation in rat auditory cortex are preserved across NREM and REM sleep. Cerebral cortex, 25(5), 1362–1378.
de Vivo, L., Faraguna, U., Nelson, A., Pfister-Genskow, M., Klapperich, M., Tononi, G., & Cirelli, C. (2014). Developmental patterns of sleep slow wave activity and synaptic density in adolescent mice. Sleep, 37(4), 689.
Tononi, G., & Cirelli, C. (2014). Sleep and the price of plasticity: from synaptic and cellular homeostasis to memory consolidation and integration. Neuron, 81(1), 12–34.
Vyazovskiy, V., Cui, N., Rodriguez, A., Funk, C., Cirelli, C., & Tononi, G. (2014). The dynamics of cortical neuronal activity in the first minutes after spontaneous awakening in rats and mice. Sleep, 37(8), 1337.
Bellesi, M., Riedner, B., Garcia-Molina, G., Cirelli, C., & Tononi, G. (2014). Enhancement of sleep slow waves: underlying mechanisms and practical consequences. Frontiers in systems neuroscience, 8.
Nere, A., Hashmi, A., Cirelli, C., & Tononi, G. (2013). Sleep-dependent synaptic down-selection (I): modeling the benefits of sleep on memory consolidation and integration. Frontiers in neurology, 4.
Bellesi, M., Pfister-Genskow, M., Maret, S., Keles, S., Tononi, G., & Cirelli, C. (2013). Effects of sleep and wake on oligodendrocytes and their precursors. The Journal of Neuroscience, 33(36), 14288–14300.
Tononi, G., & Cirelli, C. (2013). During sleep, the brain weakens the connections among nerve cells, apparently conserving energy and, paradoxically, aiding memory. Scientific American, 309(2), 34–9.
Nelson, A., Faraguna, U., Zoltan, J., Tononi, G., & Cirelli, C. (2013). Sleep patterns and homeostatic mechanisms in adolescent mice. Brain sciences, 3(1), 318–343.
Cirelli, C. (2013). Sleep and synaptic changes. Curr Opin Neurobiol, 23(5), 841–6.
Vyazovskiy, V., Olcese, U., Cirelli, C., & Tononi, G. (2013). Prolonged wakefulness alters neuronal responsiveness to local electrical stimulation of the neocortex in awake rats. Journal of sleep research, 22(3), 239–250.
Hung, C.S., Sarasso, S., Ferrarelli, F., Riedner, B., Ghilardi, M., Cirelli, C., & Tononi, G. (2013). Local experience-dependent changes in the wake EEG after prolonged wakefulness. Sleep, 36(1), 59–72.
Dash, M., Bellesi, M., Tononi, G., & Cirelli, C. (2013). Sleep/wake dependent changes in cortical glucose concentrations. Journal of neurochemistry, 124(1), 79–89.
Dash, M., Tononi, G., & Cirelli, C. (2012). Extracellular levels of lactate, but not oxygen, reflect sleep homeostasis in the rat cerebral cortex. Sleep, 35(7), 909.
Tononi, G., & Cirelli, C. (2012). Time to be SHY? Some comments on sleep and synaptic homeostasis. Neural plasticity, 2012.
Andrillon, T., Nir, Y., Staba, R., Ferrarelli, F., Cirelli, C., Tononi, G., & Fried, I. (2011). Sleep spindles in humans: insights from intracranial EEG and unit recordings. The Journal of Neuroscience, 31(49), 17821–17834.
Bushey, D., & Cirelli, C. (2011). From genetics to structure to function: exploring sleep in Drosophila. Int Rev Neurobiol, 99, 213–44.
C Hanlon, E., V Vyazovskiy, V., Faraguna, U., Tononi, G., & Cirelli, C. (2011). Synaptic potentiation and sleep need: clues from molecular and electrophysiological studies. Current topics in medicinal chemistry, 11(19), 2472–2482.
Vyazovskiy, V., Cirelli, C., & Tononi, G. (2011). Electrophysiological correlates of sleep homeostasis in freely behaving rats. Progress in brain research, 193, 17.
Vyazovskiy, V., Olcese, U., Hanlon, E., Nir, Y., Cirelli, C., & Tononi, G. (2011). Local sleep in awake rats. Nature, 472(7344), 443–447.
Nir, Y., Staba, R., Andrillon, T., Vyazovskiy, V., Cirelli, C., Fried, I., & Tononi, G. (2011). Regional slow waves and spindles in human sleep. Neuron, 70(1), 153–169.
Bushey, D., Tononi, G., & Cirelli, C. (2011). Sleep and synaptic homeostasis: structural evidence in Drosophila. Science, 332(6037), 1576–1581.
Maret, S., Faraguna, U., Nelson, A., Cirelli, C., & Tononi, G. (2011). Sleep and waking modulate spine turnover in the adolescent mouse cortex. Nature neuroscience, 14(11), 1418–1420.
Nelson, A., Faraguna, U., Tononi, G., & Cirelli, C. (2010). Effects of anesthesia on the response to sleep deprivation. Sleep, 33(12), 1659.
Gilestro, G., Tononi, G., & Cirelli, C. (2009). Widespread changes in synaptic markers as a function of sleep and wakefulness in Drosophila. Science, 324(5923), 109–112.
Vyazovskiy, V., Cirelli, C., Pfister-Genskow, M., Faraguna, U., & Tononi, G. (2008). Molecular and electrophysiological evidence for net synaptic potentiation in wake and depression in sleep. Nature neuroscience, 11(2), 200–208.
Faraguna, U., Vyazovskiy, V., Nelson, A., Tononi, G., & Cirelli, C. (2008). A causal role for brain-derived neurotrophic factor in the homeostatic regulation of sleep. The Journal of Neuroscience, 28(15), 4088–4095.
Bushey, D., Huber, R., Tononi, G., & Cirelli, C. (2007). Drosophila Hyperkinetic mutants have reduced sleep and impaired memory. The Journal of neuroscience, 27(20), 5384–5393.
Huber, R., Tononi, G., & Cirelli, C. (2007). Exploratory behavior, cortical BDNF expression, and sleep homeostasis. Sleep, 30(2), 129–139.
Cirelli, C. (2005). A molecular window on sleep: changes in gene expression between sleep and wakefulness. The Neuroscientist, 11(1), 63–74.
Cirelli, C., Bushey, D., Hill, S., Huber, R., Kreber, R., Ganetzky, B., & Tononi, G. (2005). Reduced sleep in Drosophila Shaker mutants. Nature, 434(7037), 1087–1092.
Cirelli, C., LaVaute, T., & Tononi, G. (2005). Sleep and wakefulness modulate gene expression in Drosophila. Journal of neurochemistry, 94(5), 1411–1419.
Cirelli, C., Gutierrez, C., & Tononi, G. (2004). Extensive and divergent effects of sleep and wakefulness on brain gene expression. Neuron, 41(1), 35–43.
Huber, R., Hill, S., Holladay, C., Biesiadecki, M., Tononi, G., & Cirelli, C. (2004). Sleep homeostasis in Drosophila melanogaster. Sleep, 27(4), 628–639.
Cirelli, C. (2003). Searching for sleep mutants of Drosophila melanogaster. Bioessays, 25(10), 940–949.