Neocortical long-range inhibition promotes cortical synchrony and sleep

Abstract Sleep and wakefulness are associated with distinct cortical patterns of rhythmic activity 1 . During low-arousal states such as slow-wave sleep, synchronous low-frequency rhythms dominate activity across widespread cortical regions. Although inhibitory neurons are increasingly recognized as key regulators of cortical state 2–4 , the circuit mechanisms that coordinate synchronized activity across local and distant neocortical networks in vivo remain poorly understood. Here we show in mice that cells co-expressing somatostatin (Sst) and chondrolectin (Chodl)—which constitute a sparse and genetically distinct class of neocortical GABAergic inhibitory neurons—are selectively active during low-arousal states and mostly silent during periods of high arousal. In contrast to most neocortical inhibitory neurons, Sst-Chodl cells, despite being extremely sparse, exert widespread influence across the neocortex, through long-range axons that target multiple regions simultaneously. Selective activation of Sst-Chodl cells is sufficient to promote the multi-region cortical synchronization that is characteristic of low-arousal states and to induce sleep. Together, these findings show that long-range Sst-Chodl inhibitory neurons not only track behavioural state, but can also actively promote synchronized cortical activity and sleep behaviour, highlighting that cortical circuits have a key role in sleep regulation, alongside established subcortical mechanisms.

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Publication Details

Journal
Nature
Published
2026-09-09
DOI
https://doi.org/10.1038/s41586-026-10876-y
Primary Topic
Sleep and Wakefulness Research
Type
article
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article

Neocortical long-range inhibition promotes cortical synchrony and sleep

Jacob M Ratliff, John Ngai, Soyoun Kim, Hongkui Zeng et al.
Nature
Sleep and Wakefulness Research
article

Neocortical long-range inhibition promotes cortical synchrony and sleep

Jacob M Ratliff, John Ngai, Soyoun Kim, Hongkui Zeng, Bosiljka Tasic, Bianca Stith, Karl Deisseroth, Lief E. Fenno, Charu Ramakrishnan, Geoffrey Terral, Staci A. Sorensen, David Stafford, Renata Batista‐Brito, Lucas Sjulson, Stephanie Rudolph, Stefano Lutzu, Thomas S. Kilduff, Nelson A. Perez-Catalan, Arenski Vazquez, Julie Mota, Gabriela Neubert da Silva, Arena Manning, Tanya Daigle, Matt Mallory, Gianna Mattessich
article en

Abstract

Abstract Sleep and wakefulness are associated with distinct cortical patterns of rhythmic activity 1 . During low-arousal states such as slow-wave sleep, synchronous low-frequency rhythms dominate activity across widespread cortical regions. Although inhibitory neurons are increasingly recognized as key regulators of cortical state 2–4 , the circuit mechanisms that coordinate synchronized activity across local and distant neocortical networks in vivo remain poorly understood. Here we show in mice that cells co-expressing somatostatin (Sst) and chondrolectin (Chodl)—which constitute a sparse and genetically distinct class of neocortical GABAergic inhibitory neurons—are selectively active during low-arousal states and mostly silent during periods of high arousal. In contrast to most neocortical inhibitory neurons, Sst-Chodl cells, despite being extremely sparse, exert widespread influence across the neocortex, through long-range axons that target multiple regions simultaneously. Selective activation of Sst-Chodl cells is sufficient to promote the multi-region cortical synchronization that is characteristic of low-arousal states and to induce sleep. Together, these findings show that long-range Sst-Chodl inhibitory neurons not only track behavioural state, but can also actively promote synchronized cortical activity and sleep behaviour, highlighting that cortical circuits have a key role in sleep regulation, alongside established subcortical mechanisms.

Nature
SRI International (US), National Institutes of Health (US), Albert Einstein College of Medicine (US), Allen Institute for Brain Science (US), Howard Hughes Medical Institute (US), National Institute of Neurological Disorders and Stroke (US), Allen Institute (US), The University of Texas at Austin (US), University of California, Berkeley (US), Stanford University (US)
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