Summary: A new study brings researchers closer to understanding how the brain flips a switch to wake us from sleep.
Source: University of Oxford.
Researchers at Oxford University have identified the mechanism that flips a neural “sleep switch,” revealing how the brain transitions from sleep to wakefulness. The findings, published in Nature, provide fresh insight into the elusive sleep homeostat.
Sleep is regulated by two interacting systems: the circadian clock, which times sleep to the daily light–dark cycle, and the sleep homeostat, which monitors the need for sleep and triggers sleep when that need reaches a certain level. While the circadian clock has been well characterized, the homeostat’s internal signal has remained obscure.
Professor Gero Miesenböck, whose laboratory led the work, described the two systems this way: the circadian clock helps us anticipate predictable environmental changes caused by Earth’s rotation and thus schedules sleep at times that are least disruptive. The sleep homeostat, by contrast, appears to measure some internal variable that builds during wakefulness; once that variable reaches a threshold, the brain initiates sleep and resets the system.
The team investigated the sleep homeostat in Drosophila melanogaster (fruit flies), a model organism that helped establish the genetic basis of the circadian clock decades ago. Each fly has roughly two dozen sleep-control neurons in a brain region called the dorsal fan-shaped body (dFB). These neurons are believed to be homologous to sleep-regulating cells in other animals, possibly including humans. When dFB neurons are electrically active, the fly displays sleep; when these neurons are silent, the fly is awake.
To probe how the switch operates, the researchers used optogenetics, a method pioneered by Miesenböck that uses pulses of light to control neuronal activity. In this study, optogenetic stimulation was applied to dopaminergic neurons to trigger dopamine release. In both flies and mammals, dopamine is a key neuromodulator associated with arousal—psychostimulant drugs that increase dopamine levels promote wakefulness.
Activation of the dopaminergic system caused the dFB sleep neurons to fall silent and the flies to wake. When dopamine signaling was halted and allowed to dissipate, the dFB neurons returned to their electrically active state and the flies resumed sleep. The researchers describe the sleep switch as a hard, all-or-none mechanism: the system rapidly moves between ON (sleep) and OFF (wake) states rather than lingering in intermediate twilight states.
The study identified a specific ion channel that mediates this switch. The channel, which the team named Sandman, is a two-pore-domain potassium channel encoded by the gene CG8713. In the sleep-promoting ON state, Sandman is retained inside the cell. Dopamine triggers Sandman to translocate to the neuronal membrane, increasing leak potassium conductance, effectively short-circuiting the neurons and driving them into electrical silence to produce wakefulness.
Complementary changes in other ion currents were also observed: voltage-gated A-type currents carried by Shaker and Shab channels are downregulated during the transition to silence, while Sandman-dependent leak currents are upregulated. Manipulating expression of Shaker or Sandman in dFB neurons altered sleep behavior in predictable ways—reducing Shaker slowed ON-state firing and reduced sleep, whereas reducing Sandman impaired the OFF transition and increased sleep.
Dr Diogo Pimentel, a lead author, commented that direct control of the sleep switch enabled the team to dissect how it works. Lead author Dr Jeff Donlea likened the mechanism to a thermostat: instead of sensing temperature to control heating, the homeostatic sleep switch senses an internal signal that, when it exceeds a set point, activates sleep-promoting neurons until the need is reset.
Professor Miesenböck emphasized the remaining mystery: what exactly does the sleep homeostat measure? Identifying that physiological variable—what fills the homeostatic meter during wakefulness—would be a major advance toward explaining why sleep is necessary.
Source: University of Oxford
Image Source: Centre for Neural Circuits and Behaviour (credited by Neuroscience News)
Video Source: CNCB (video material credited to CNCB)
Abstract (summary)
The study “Operation of a homeostatic sleep switch” demonstrates how a small population of dFB neurons in Drosophila switches between electrically active and quiescent states to regulate sleep homeostasis. Dopamine acts as an arousing neuromodulator that drives the switch via Dop1R2 receptors and potassium conductances. The OFF transition to wakefulness requires translocation of the two-pore-domain potassium channel Sandman to the plasma membrane, while ON-state activity depends on voltage-gated A-type currents through Shaker and Shab. Genetic manipulation of these channels in dFB neurons alters sleep behavior, linking specific biophysical changes in a compact neural circuit to the control of sleep–wake state.
“Operation of a homeostatic sleep switch” by Diogo Pimentel, Jeffrey M. Donlea, Clifford B. Talbot, Seoho M. Song, Alexander J. F. Thurston and Gero Miesenböck in Nature. Published online August 3, 2016. doi:10.1038/nature19055
University of Oxford. “Researchers Discover Sandman’s Role in Sleep Control.” Neuroscience News. 3 August 2016.