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Flipping the sleep switch

Nature volume 536, pages 278280 (18 August 2016) | Download Citation

  • A Correction to this article was published on 14 September 2016

This article has been updated

Inactivation of a group of sleep-promoting neurons through dopamine signalling can cause acute or chronic wakefulness in flies, depending on changes in three different potassium-channel proteins. See Letter p.333

Many people have nodded off during a long road trip, or lain in bed desperately trying to fall asleep. These experiences illustrate real-world consequences of an improperly maintained balance between sleep- and wake-promoting neural circuits. On page 333, Pimentel et al.1 describe the identification of a bona fide molecular switch that allows wake-promoting signals to turn off individual sleep-promoting neurons to regulate waking. These findings open up avenues for understanding the complexity of sleep regulation in healthy individuals and during disease.

Multiple sleep and wake circuits are found throughout the mammalian central nervous system and are believed to interact in a mutually inhibitory manner2,3. A similar organization is found in the fruitfly Drosophila, in which independent sleep and wake centres cooperate to produce stable sleep and wake patterns. Flies are less complex than mammals, and their neuronal circuits can be easily manipulated using genetic tools, making them more tractable as study subjects.

Perhaps the best-characterized sleep centre in flies is composed of neurons that project into a brain region called the dorsal fan-shaped body (dFB)4,5,6. The wake-promoting neurons (dopaminergic neurons) in the fly's brain release the neurotransmitter molecule dopamine. To better understand the molecular logic used by these two sets of neurons to regulate the sleep-to-wake transition, Pimentel et al. stimulated the wake-promoting neurons to release dopamine while they simultaneously recorded the activity of the sleep-promoting dFB neurons.

The authors genetically engineered the flies' dopaminergic neurons so that their activity could be modulated by a pulse of light — a technique known as optogenetics. Flies were restrained by fixing their heads, such that they could freely move their legs on a treadmill when awake. With this set-up, the physiological activity of the sleep-promoting dFB neurons and their response to the activation of dopaminergic wake-promoting neurons could be studied in real time.

When a fly spontaneously went to sleep for at least five minutes, the researchers optogenetically activated its dopaminergic neurons and measured the effect on the dFB neurons. In the sleeping flies, in the absence of dopamine signalling, the dFB neurons showed spikes of activity, which the researchers term the 'ON' state (Fig. 1a). Following acute activation of their dopaminergic neurons, the flies rapidly awoke. Pimentel and colleagues found that the dFB neurons were transiently hyperpolarized at this point (that is, the electrical potential across the cells' membranes sharply decreased), which inhibited neuronal firing. This change in membrane potential was brought about by a movement of potassium ions out of the cell through an unidentified potassium-channel protein.

Figure 1: Switch off to wake up.
Figure 1

a, Pimentel et al.1 report that, during sleep, neurons in the brain's dorsal fan-shaped body (dFB) in flies are in an ON state. An unidentified potassium-channel protein is closed, so potassium ions remain in the cell, and the dopamine receptor protein Dop1R2 is inactive. In this state, dFB neurons show repetitive bursts of activity known as spiking (displayed as peaks in a graph of electrical activity). b, After transient dopamine release from wake-promoting neurons (not shown), the neurotransmitter molecule binds to and activates Dop1R2, triggering signalling through the protein Gi/o. This in turn opens and causes potassium efflux through the channel protein, producing a current across the cell membrane that acutely inhibits spiking. Animals rapidly awaken while neurons remain in the ON state. c, Prolonged exposure to dopamine triggers an OFF state, in which the activity of two other potassium channels is modulated. One channel, Shaker, is inhibited (not shown), and another channel protein, Sandman, moves from vesicles in the cytoplasm to the membrane. Potassium efflux through Sandman then chronically inhibits neuronal firing.

Next, Pimentel et al. applied dopamine directly to dFB dendrites — projections that receive signals from other neurons and transmit them to the body of the dFB neuron. Again, they observed hyperpolarization and suppression of firing, confirming that the effects of optogenetic activation reflected the direct consequences of increased dopamine signalling. The authors mapped this response to the Dop1R2 dopamine receptor protein, which is expressed in dFB neurons. Moreover, pharmacological and genetic studies demonstrated that Dop1R2 activation by dopamine inhibits dFB spiking through the Gi/o signalling pathway, which in turn modulates physiological properties of the neuron. Thus, the researchers have found a molecular mechanism by which a wake-promoting dopamine signal directly and acutely inhibits dFB spiking during the ON state, allowing flies to rapidly wake up as environmental conditions demands (Fig. 1b).

In addition to this acute response, Pimentel and colleagues showed that longer exposures to dopamine turned off sleep-promoting neurons for extended periods of time. In this setting, dopamine hyperpolarized and inhibited spiking of dFB neurons by modulating the activity of two other potassium channels — one called Shaker and one dubbed Sandman by the authors. During prolonged exposure to dopamine, Sandman channels, which are normally retained in intracellular vesicles, are inserted into the membrane to chronically inhibit dFB firing. Following chronic inhibition, dFB neurons became impervious for up to an hour to a variety of stimuli that ordinarily trigger neuronal impulses . This 'OFF' state persisted even in the absence of a steady supply of dopamine, and produced a prolonged period of insomnia (Fig. 1c). Thus, the arousing effects of dopamine occur through two distinct mechanisms that operate on different timescales.

These results are truly exciting because they describe how circuit interactions are integrated at the level of individual neurons to maintain stable sleep–wake patterns. These types of analysis, particularly as they pertain to sleep, have proved to be inherently difficult in more-complex animals7. It will be interesting now to turn to mammals, looking at various types of sleep-promoting neuron to determine whether the switching mechanisms identified by Pimentel et al. in flies have similar roles in a more complex setting. In particular, it remains to be seen how this molecular-switching mechanism can be integrated into models that conceptualize sleep regulation as a winner-takes-all competition between opposing sleep-promoting and wake-promoting circuits2.

Many avenues for further investigation remain. First, it will be interesting to find the switching mechanism that mediates the transition from waking to sleep, which has obvious clinical utility for conditions such as insomnia and Alzheimer's disease. Second, the dFB is made up of diverse populations of neurons that receive information from a large variety of neurotransmitters and neuropeptide molecules8 — understanding how dopamine signalling interacts with these other neuroactive compounds will be crucial for truly understanding the molecular logic that underlies sleep regulation.

In summary, Pimentel and colleagues' study is valuable not only for the answers that it has given, but also because it provides the tools and logical framework that open up an area of enquiry that will be fruitful for many years to come. In particular, the ability to target a more precise molecular mechanism in discrete sets of neurons may make it easier to develop better drugs to enhance both sleep and waking with fewer adverse side effects.

Notes

Change history

  • 14 September 2016

    The number of potassium-channel proteins was given incorrectly. This has now been amended.

References

  1. 1.

    et al. Nature 536, 333–337 (2016).

  2. 2.

    , & Nature 437, 1257–1263 (2005).

  3. 3.

    Handb. Clin. Neurol. 98, 131–149 (2011).

  4. 4.

    , , , & Science 332, 1571–1576 (2011).

  5. 5.

    , , , & Curr. Biol. 22, 2114–2123 (2012).

  6. 6.

    et al. Nature Neurosci. 15, 1516–1523 (2012).

  7. 7.

    , & Front. Neurol. 6, 32 (2015).

  8. 8.

    & J. Comp. Neurol. 519, 290–315 (2011).

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  1. Stephane Dissel and Paul J. Shaw are in the Department of Neuroscience, Washington University School of Medicine in St. Louis, St. Louis, Missouri 63110, USA.

    • Stephane Dissel
    •  & Paul J. Shaw

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Correspondence to Stephane Dissel or Paul J. Shaw.

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