Summary: Reduced levels of the HDAC4 enzyme caused mice to sleep longer and with greater depth than normal.
Source: University of Tsukuba
A good night’s sleep benefits both mind and body, but what determines how long we need to sleep and what controls sleep depth?
A new study from researchers at the University of Tsukuba identifies a cellular signaling pathway in the brain that regulates both how long animals sleep and how deep that sleep is. By studying genetic mutations in mice, the team uncovered molecular links that influence sleep quantity and quality.
“We examined genetic mutations in mice and how these affect their patterns of sleep,” says senior author Professor Hiromasa Funato. The researchers discovered a mutation that caused mice to sleep significantly longer and more deeply. This change was traced to lower levels of the enzyme histone deacetylase 4 (HDAC4), a protein known to repress the activity of certain genes.
Earlier work has shown that HDAC4 activity is controlled by phosphorylation—the attachment of phosphate groups—which alters its location within the cell and reduces its ability to suppress target proteins. The team asked whether HDAC4 phosphorylation affects sleep regulation.
“We focused on a protein called salt-inducible kinase 3, SIK3, which phosphorylates HDAC4,” explains Professor Funato. The researchers had previously observed strong links between SIK3 and sleep. In the current study, mice lacking SIK3 or carrying an HDAC4 variant resistant to phosphorylation displayed reduced sleep. Conversely, animals with an overactive form of SIK3 showed increased HDAC4 phosphorylation and slept substantially more. The investigators also identified LKB1 as an upstream kinase that phosphorylates SIK3; when LKB1 was deficient, similar reductions in sleep were observed.
Together, these results point to a signaling cascade spanning LKB1 to SIK3 to HDAC4. “This pathway promotes the phosphorylation of HDAC4, which in turn appears to favor sleep, likely by altering the expression of genes that promote sleep,” says co-senior author Professor Masashi Yanagisawa.
To pinpoint where in the brain this pathway acts, the team manipulated SIK3 and HDAC4 levels in specific cell types and brain regions. Their experiments showed that signaling within cortical neurons primarily regulates sleep depth, while signaling in the hypothalamus influences the total amount of deep, non-rapid eye movement sleep (NREMS). In both regions, excitatory neurons—cells that activate other neurons—were identified as key players in controlling sleep metrics.
These findings help bridge intracellular molecular events with circuit-level control of sleep. By identifying HDAC4 as a sleep-regulating molecule and mapping the LKB1–SIK3–HDAC4 cascade to specific excitatory neurons in cortex and hypothalamus, the study clarifies distinct mechanisms that govern NREMS quantity and NREMS depth.
The study, published in Nature, advances our understanding of how sleep is regulated at the molecular and cellular levels. This improved insight could inform future research into sleep disorders and guide development of new treatment strategies that target these intracellular signaling pathways.
About this sleep research news
Author: Press Office, University of Tsukuba
Source: University of Tsukuba
Contact: Press Office – University of Tsukuba
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Original Research: Closed access. “Kinase signalling in excitatory neurons regulates sleep quantity and depth” by Staci J. Kim et al., Nature
Abstract
Kinase signalling in excitatory neurons regulates sleep quantity and depth
Advances have clarified many circuit-level mechanisms that control sleep and wakefulness, but the intracellular signaling pathways and the specific neuron groups they operate in were less well understood. Using a forward genetics approach in mice, this study identifies histone deacetylase 4 (HDAC4) as a molecule that regulates sleep.
Haploinsufficiency of Hdac4, which is a substrate of SIK3, increased sleep. By contrast, mice lacking SIK3 or its upstream kinase LKB1 in neurons, or mice carrying an Hdac4S245A mutation that prevents phosphorylation by SIK3, showed reduced sleep. These results indicate that the LKB1–SIK3–HDAC4 cascade is a critical intracellular pathway for regulating sleep and wakefulness.
Targeted manipulations revealed that SIK3 signaling in excitatory neurons of the cerebral cortex and hypothalamus positively regulates EEG delta power during NREMS and the amount of NREMS, respectively. A common set of transcripts biased toward synaptic function was regulated in cortical glutamatergic neurons both by expression of a gain-of-function Sik3 allele and by sleep deprivation.
Overall, the findings suggest that different groups of excitatory neurons regulate NREMS quantity and depth through shared intracellular signals, providing a framework that links molecular signaling events with circuit-level control of non-rapid eye movement sleep.