Using Fruit Flies to Study the Genetic Basis of Sleep Regulation
Bill Joiner, University of California, San Diego, USA

Invertebrate model organisms like the fruit fly are powerful systems for investigating the genetic basis of sleep regulation. Using a simple locomotor-based activity monitoring system, my lab and others have reduced or disrupted gene function throughout the fruit fly genome to identify genes that control sleep. One such effort led to the identification of a previously uncharacterized molecule we named sleepless. Disruption of the sleepless gene causes a severe reduction in total sleep as well as the inability of animals to recover lost sleep following periods of sleep deprivation, a process known as homeostatic control of sleep need. The predicted structure of the protein encoded by sleepless resembles neurotoxins that often act on molecules responsible for electrical signaling among neurons. This structural similarity led us to search for and identify proteins that are controlled by sleepless to regulate neuronal activity and thereby regulate sleep. Recently we have shown that the sleepless regulatory pathway seems to be conserved from flies to mammals: sleepless-related genes regulate electrical signaling in mice as they do in fruit flies.

Despite such examples of progress, several major challenges to studying the biological basis of sleep remain. The first is to define brain circuitry that is necessary for regulation of sleep in invertebrates so that genes of interest can be studied in the relevant cellular context. This point relates to the second major challenge in this field, which is to distinguish between genes necessary for functioning of brain regions that control sleep and genes that actually respond to sleep need. Current strategies may be adept at identifying the former but not necessarily the latter. A third major challenge is to identify how these genes transmit sleep need to changes in neuronal function. Finally, our understanding of the biological basis of sleep, like many other complex phenomena controlled by the brain, would benefit from the ability to measure the activity of populations of neurons simultaneously so that circuitry analysis, genetics and behavior could be combined in one experimental paradigm. The limited size and complexity of invertebrate nervous systems may be particularly amenable to meeting this last challenge with the development of promising optical imaging technologies.

As these challenges are met, invertebrate research is likely to continue to enhance our understanding of nervous system function in mammals. Our work with sleepless is but one example of how many discoveries simply could not have been made easily in mammals without information gleaned from invertebrates to tell us what to look for. Our studies illustrate another important point as well: genes that regulate sleep are likely to regulate electrical signaling in neurons. Identification of these genes may thus lead to discoveries of novel targets for pharmacological intervention in disorders of the nervous system.

References:

1. Shaw, P. J., Cirelli, C., Greenspan, R. J., and Tononi, G. Science 287, 1834-1837, 2000.

2. Hendricks, J. C., Finn, S. M., Panckeri, K. A., Chavkin, J., Williams, J. A., Sehgal, A., and Pack, A. I. Neuron 25, 129-138, 2000.

3. Nitz, D. A., van Swinderen, B., Tononi, G., and Greenspan, R. J. Curr Biol 12, 1934-1940, 2002.

4. Koh, K., Joiner, W.J., Wu, M.N., Yue, Z., Smith, C.J., and Sehgal, A. Science 321, 372-6, 2008.

5. Wu, M.N., Joiner, W.J., Dean, T., Yue, Z., Smith, C.J., Chen, D., Hoshi, T., Sehgal, A., and Koh, K. Nat Neurosci 13, 69-75, 2010.

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