The Conversations in Science Series brings together UW-Madison researchers and Dane County teachers in order to foster significant connections. Now in its 10th year, the Series is designed to provide personal enrichment to teachers in a wide range of areas related to science, technology and society, and to enable researchers and educators to share their expertise with the Dane County community.

ABOUT THE CONVERSATION

Sleep is a universal behavior that has been demonstrated in every animal species studied, from insects to mammals. It is one of the most significant of human behaviors, occupying roughly one-third of our lives. Sleep is clearly necessary for survival since prolonged sleep deprivation leads to severe physical and cognitive impairment, and finally death. Manipulations of sleep have profound impacts on mood, memory and behavior. The exact function (or functions) of sleep, however, remains a mystery. Yet, we know that although the entire body benefits from sleep, the most immediate, unavoidable effect of sleep deprivation is cognitive impairment, suggesting that sleep is first and foremost for the brain. Indeed, recent evidence suggests that sleep has a core function involving the brain, and that such a function might be identifiable at the cellular level. I will discuss this new evidence, suggesting that the brain cells that are involved in learning during the day are those more in need of sleep the following night.

ABOUT THE SPEAKER

I received my Ph.D. in Neuroscience, Scuola Superiore S.Anna and University of Pisa, Italy.

Long-term research goal of the laboratory
My research aims at understanding the function of sleep and clarifying the functional consequences of sleep loss. I believe that the key to understanding sleep is to be found at the intersection between the cellular and the system’s level. This is why my laboratory 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.
Lines of work
1. Identification of genes involved in sleep regulation using forward genetics in Drosophila. We and others have recently demonstrated that fruit flies sleep and need sleep in much the same way as mammals do (Shaw et al., 2000; Hendricks et al., 2000; Huber et al., 2004; Cirelli et al., 2005a,b). 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 our laboratory has performed a large-scale mutagenesis screening for sleep phenotypes in Drosophila. Our goal is to identify flies that need little sleep as well as flies that are resistant to sleep deprivation. We have screened so far more than 10,000 mutant lines (> 150,000 individual flies) and identified several candidate lines (Cirelli, 2003). We are now performing the necessary molecular and genetic characterization of such mutant lines. The characterization of one of the most extreme short sleeper mutants has just been completed (Cirelli et al., 2005a). This study demonstrated that a point mutation in the voltage-sensing module of the voltage-dependent potassium channel Shaker abolishes the Shaker current and decreases sleep from 900 to 300min/day. Thus, Shaker appears to be a key regulator of sleep amount in fruit flies. Importantly, Shaker-like channels are also present in mammals, and we are currently studying their role in mammalian sleep regulation using mice and rats.
2. Molecular correlates of sleep and spontaneous wakefulness. Our laboratory 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 we have pursued such genome-wide screening using high-density DNA microarrays in fruit flies, rats, hamsters and humans. In rats, we have found that hundreds of genes are differentially expressed in the brain during sleep and waking (Cirelli et al., 2004). 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 we have found that molecular correlates of sleep and wakefulness are also present in flies, and that they are often similar to those described in rats (Cirelli et al., 2005b).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 wakefulness and low during sleep (Cirelli et al., 1996; 2000, 2004). High noradrenaline levels during wakefulness 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.
3. Molecular correlates of sleep deprivation. In a recent transcriptomic analysis of the brain of rats sleep deprived for several days we have found that prolonged sleep loss induces the expression of several antibodies, including autoantibodies, and glial genes. We are now performing additional experiments to determine whether continuous wakefulness may be detrimental to glial functions. We 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. Finally, we have just started a large-scale proteomic profiling in flies, rats, and sparrows. The goal is to identify brain proteins specifically affected by sleep loss.
4. The synaptic homeostasis hypothesis. The results of these and other studies have prompted a new hypothesis about the functions of sleep that needs to be examined through follow-up experiments. Specifically, we 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 (Tononi and Cirelli, 2005) is being tested at several different levels in a joint effort with the laboratory of Dr. Giulio Tononi. Dr. Tononi’s team uses computer simulations and performs human experiments with high-density EEG and transcranial magnetic stimulation. Dr. Cirelli’s team uses flies, mice and rats to test the hypothesis at a molecular, behavioral, and electrophysiological level. In a recent experiment in rats we have found that a waking period associated with reduced neural plasticity results in a blunted induction of plasticity-related genes and is followed by a sleep period of reduced intensity (Cirelli et al., 2005c). We are now determining whether the converse is also true, i.e. whether an increase in synaptic potentiation during waking is associated with a stronger induction of plasticity-related genes and is followed by a sleep period of increased intensity. Moreover, we are studying specific molecular markers of synaptic depression to determine whether sleep is indeed associated with a decrease in synaptic strength.

Suggested Reading

Normal Human Sleep at Different Ages: Infants to Adolescents -- Chapter 1

Is Sleep Essential?