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Kinase signalling in excitatory neurons regulates sleep quantity and depth
Staci J Kim1, Noriko Hotta-Hirashima1, Fuyuki Asano1
1International Institute for Integrative Sleep Medicine (WPI-IIIS), University of Tsukuba, Tsukuba, Ibaraki, Japan.
Nature
|December 8, 2022
Summary
Researchers identified a new molecular pathway, LKB1-SIK3-HDAC4, that regulates sleep and wakefulness. This signaling cascade involves histone deacetylase 4 (HDAC4) and impacts non-rapid eye movement sleep (NREMS) quantity and depth.
Area of Science:
- Neuroscience
- Molecular Biology
- Genetics
Background:
- Understanding the molecular mechanisms governing sleep and wakefulness is crucial for addressing sleep disorders.
- While neurocircuitry of sleep is known, intracellular pathways remain largely uncharacterized.
Purpose of the Study:
- To identify novel intracellular signaling molecules and pathways regulating sleep and wakefulness.
- To elucidate the role of specific neuron groups in sleep regulation.
Main Methods:
- Forward genetics screen in mice to identify sleep-regulating genes.
- Genetic manipulation of specific genes (LKB1, SIK3, HDAC4) in neurons.
- Analysis of electroencephalogram (EEG) delta power and sleep amount.
Main Results:
- Histone deacetylase 4 (HDAC4) was identified as a key sleep-regulating molecule.
- The LKB1-SIK3-HDAC4 signaling cascade was found to control sleep and wakefulness.
- SIK3 signaling in cortical and hypothalamic excitatory neurons regulates NREMS quantity and EEG delta power.
Conclusions:
- The LKB1-SIK3-HDAC4 pathway is a critical regulator of sleep and wakefulness.
- Distinct excitatory neuron populations in the cortex and hypothalamus utilize common intracellular signals to control NREMS.
- This study bridges intracellular events with circuit-level mechanisms of NREMS regulation.
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