Remembering the need for sleep
April 2, 2025
Sleep is the only ubiquitous behaviour whose function remains unknown. The Miesenböck group is looking for—and finding—clues to the mystery of sleep in the properties of sleep-inducing cells in the brain.
Nervous systems delegate the task of detecting and correcting sleep deficits to a minority of specialized cells. Like circuit breakers, these neurons keep a watch on a sleep-relevant aspect of their own physiology and trip the rest of the brain into sleep before a widespread overload occurs. Discovering what variable sleep-control cells are monitoring could be the smoking gun in understanding the function of sleep.
Writing in Nature, Olof Rorsman, Gero Miesenböck and colleagues report that sleep-inducing neurons in the brains of fruit flies respond to breakdown products of peroxidized lipids. The neurons contain machinery that increases their electrical discharge when lipid-derived carbonyls (such as 4-ONE) accumulate. The centrepiece of this machinery is the ancillary β-subunit of a voltage-gated potassium channel, which flips back and forth between two states, forming a digital memory that can hold a single bit of information. The memory stores brief exposures to lipid peroxidation products by switching from one state (bit ‘0’) to the other (bit ‘1’) and is reset by membrane depolarization.
The operational logic resembles that of a semiconductor random access memory, which holds a single bit of information as an electric charge on a storage capacitor, which is erased when the voltage across the gate of its access transistor goes high.
The authors suggest that sleep-control neurons use this mechanism to encode their recent lipid peroxidation history in the collective binary states of their potassium channel β-subunits. During waking, electrons leak from the respiratory chains of the inner mitochondrial membrane, producing superoxide and other reactive oxygen species (ROS), which attack the polyunsaturated fatty acyl chains of membrane lipids. The β-subunit population keeps a tally of the resulting membrane damage. This biochemical memory (which the authors equate to the accumulated sleep pressure) is read out and erased during subsequent sleep-promoting electrical activity, with the firing rate determined by the fraction of channels previously set to bit ‘1’.
In an incisive demonstration of how lipid peroxidation dictates the need for sleep, the authors examined mutant flies that cannot rid their brains of lipid-derived carbonyls. They found that the animals were almost always asleep. “The poor mutants literally doze away their lives”, says Rorsman, “because their lipid peroxidation memories are always full.”
The work was funded by the European Research Council, the UK Medical Research Council, and Wellcome; it involved a collaboration with chemists at Justus-Liebig-Universität Giessen in Germany.
Read the full paper here.