Sleep pressure accumulates in a voltage-gated lipid peroxidation memory

Transient photocurrents in a subthreshold evidence accumulator accelerate perceptual decisions

Gero Miesenböck elected to the US National Academy of Sciences

Gero Miesenböck was one of 30 international members who—along with 120 regular members—were elected to the US National Academy of Sciences on 29 April 2025.

In a reaction, Gero said: ‘Beyond the delight of being invited into the company of distinguished colleagues, it is nice to form a thread in the international fabric of science, especially with everything that’s going on right now.’

Remembering the need for sleep

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.

Mark H. Ellisman

Abstract:  New contrasting methods, imaging tools, and data analysis strategies allow the observation of otherwise complex or hidden relationships between cellular, subcellular, and molecular constituents of cells and tissues. I will describe how advances in multi-tilt electron tomography, the development of new probes for correlated light microscopy, X-ray micro-CT, correlated multi-ion mass spectroscopy imaging and electron microscopy, and state-of-the-art 3D EM technologies add to our knowledge of structure and function in complex biological systems. Recent accomplishments include the determination of the higher-order structure and functional organization of chromatin in intact cell nuclei; the analysis of actin-associated structures within dendritic spines; and analyses of the extracellular matrix (ECM) around multiple synapse types in mammalian brains. The ECM work explores Roger Tsien’s theory that the brain stores life-long memories by regulating the activity of extracellular proteases and thereby influences the locations and relative strengths of synapses over a lifespan.

Biograhpy:  Mark Ellisman is Distinguished Professor of Neurosciences/Neurology and Director of the National Center for Microscopy and Imaging Research at UCSD. In a career spanning more than 50 years, he has investigated the molecular structure and function of neurons and glia in health and disease. Ellisman and Roger Y. Tsien maintained integrated research programs for nearly 30 years, creating numerous probes and systems for correlated light and electron microscopy. These innovations enabled studies of the dynamics of the nervous system across spatial and temporal scales.

James Jeanne

Abstract:  Parallel processing is a major source of computational power in the brain. Accordingly, connectomes of complete circuits uncover many anatomical pathways for information flow. How do different pathways implement different processing? While differences in connectivity are clearly important, differences in synaptic inhibition, short-term synaptic plasticity, and intrinsic cellular biophysics are all likely to contribute as well. However, linking these mechanisms to the circuit-level segregation of computation has been challenging. To overcome these challenges, my laboratory studies parallel processing in Drosophila olfaction, a model system where single second-order projection neurons diverge to target many third-order neurons. We use a combination of in vivo patch-clamp electrophysiology, 2-photon optogenetics, and calcium imaging from neurons with known connectivity to investigate the biophysical properties that enable and constrain signal propagation through divergent networks. I will share recent results demonstrating how olfactory coding in projection neurons is diversified by their downstream targets in the lateral horn and mushroom body, and how this depends on a striking amount of diversity in synaptic, cellular, and circuit properties. Our work is revealing how parallel processing is organized and implemented in the brain and establishes Drosophila olfaction as an invaluable experimental platform for testing its functional roles.

Biography:  James Jeanne received his BS is electrical engineering from Princeton University in 2005 and his Ph.D. in computational neuroscience from UCSD in 2012. Following postdoctoral studies with Dr. Rachel Wilson at Harvard University, he started his lab in the Neuroscience Department at Yale in 2018. His work focuses on revealing biophysical mechanisms of neural computation and behavior using the fruit fly Drosophila melanogaster, with a particular focus on synaptic and cellular dynamics.

Simone Ota

Susana Lima

Abstract:    Cyclic fluctuations in sex hormone levels intricately coordinate female sexual behavior with reproductive capacity, notably demonstrated in rodents where females only accept copulation attempts during their fertile phase. Outside this window, copulation is not only hindered by low receptivity but also actively rejected. Despite extensive research on female receptivity, rejection behavior has been largely overlooked, often dismissed as a lack of receptivity. Here I will describe a novel circuit dedicated to the cyclical control of rejection behavior situated in the ventromedial hypothalamus. Our findings suggest that a female’s sexual response to copulation attempts throughout the reproductive cycle arises from two distinct processes: receptivity and rejection. These processes are governed by separate and spatially segregated hypothalamic populations, whose activity is modulated by the reproductive cycle in a bidirectional and opposing manner.

Biography:    Susana Lima completed her PhD at Yale in 2005 (under the supervision of Gero Miesenböck) and was subsequently a postdoctoral fellow at Cold Spring Harbor Laboratory (in Tony Zador’s group) and a research fellow at Champalimaud Center for the Unknown. She became a principal investigator in 2013. Her research combines behavioral, neurophysiological and genetic approaches to study the neural circuits involved in sexual behavior.

Zvulun Elazar

Abstract: Autophagy eliminates cytoplasmic material by engulfment in membranous vesicles targeted for lysosome degradation. Non-selective autophagy coordinates the sequestration of bulk cargo with the growth of the isolation membrane (IM) through tight regulation of the rim aperture by PI(3)P. In yeast, an obligate complex of Atg24/Snx4 with Atg20 or Snx41 assembles at the IM rim in a spatially extended manner that depends on autophagic PI(3)P. This assembly stabilizes the open rim to promote autophagic sequestration of large cargo in correlation with vesicle inflation. Constriction of the rim by the PI(3)P-dependent Atg2-Atg18 complex and clearance of PI(3)P by Ymr1 antagonizes rim opening and promotes autophagic maturation and the consumption of small cargo. A second part of the talk will describe new findings on Hereditary Sensory and Autonomic Neuropathy 9 (HSAN9), a neurodegenerative disorder linked to mutations in tectonin β-propeller repeat-containing protein 2 (TECPR2) and characterized by an accumulation of mitochondrial ROS, reduced mitochondrial membrane potential, and elevated mitochondrial content that may arise from impaired autophagic clearance of aberrant mitochondria. Indeed, loss of TECPR2 led to inhibition of Pink 1- and Parkin-dependent mitophagy. The accumulation of mitochondria and the immature mitochondrial content of autophagic vesicles in the brainstem of TECPR2 knockout mice matches these cellular observations.

Biography:  Zvulun Elazar obtained his Ph.D. at the Weizmann Institute of Science and was a postdoctoral fellow at Princeton University and Memorial Sloan-Kettering Cancer Center before returning to the Weizmann Institute, where he is now Harold Korda Professor in the Department of Biological Chemistry. Elazar is a former Chair of the Scientific Council of the Weizmann Institute.

Matthias Landgraf

Abstract:  What mechanisms mediate developmental robustness in the face of inherent cellular variability, as well as diverse physical or metabolic constraints?  Focused on a developing nervous system (that of the Drosophila larva), we have been asking:  how can robust network function emerge from neuronal ensembles?

As developing networks become active, they undergo plastic tuning phases, termed ”critical periods”; ”critical” because disturbances during these developmental windows lead to lasting changes in function. To study the underlying mechanisms we have used the larval neuromuscular system as an experimental model. We find that transient embryonic experiences of different temperatures specify changes in synaptic terminal growth, neurotransmitter receptor composition and neuronal excitability. Moreover, the developmental timing of the critical period for muscles is distinct from that for neurons. We identified mitochondrial reactive oxygen species as key signals, and have preliminary insights on how such transient signals might be turned into lasting changes of gene expression and cellular properties.

Bio:  Raised in the fenlands of Northern Germany, on leaving school I emigrated to London, where I read Genetics at University College London; then embarked on a PhD in Cambridge with Prof. Michael Bate on the development of the locomotor network of Drosophila melanogaster. Following an interlude of national service (as a home care nurse in Berlin), I returned to Cambridge as a postdoctoral research fellow. In 2002 I was awarded a Royal Society University Research Fellowship, followed in 2010 by a lectureship position, then promotion to Reader and, this October, to full Professor. Our research has been funded by the Royal Society, the Wellcome Trust and the Biotechnology and Biological Sciences Research Council (BBSRC).