Decoding the Science of Optimal Sleep: A Novel Insight

Researchers from the University of Tsukuba have uncovered a neural signaling pathway that significantly impacts the duration and intensity of sleep, involving key elements like HDAC4, SIK3, and LKB1. This groundbreaking discovery could illuminate our understanding and treatment of sleep disorders.

The research team has pinpointed a specific neural signaling pathway that dictates the length and quality of our sleep.

Achieving restful sleep is critical for maintaining optimal cognitive and physical health. Yet, the scientific specifics behind sleep duration and depth have largely remained a mystery. What exactly governs our sleep quantity and quality?

Now, scientists from the University of Tsukuba in Japan have shed light on this conundrum, elucidating a neural signaling pathway that determines the extent and depth of sleep.

“In our research, we studied genetic mutations in mice and their sleep patterns,” explains the senior author of the study, Professor Hiromasa Funato. “We discovered a particular mutation that caused the mice to sleep considerably longer and deeper than usual.” The team established that this effect resulted from diminished levels of an enzyme known as histone deacetylase 4 (HDAC4), recognized for inhibiting the expression of certain genes.

Existing research on HDAC4 has illustrated that its activity is profoundly influenced by the addition of phosphate molecules in a process known as phosphorylation. This process typically results in HDAC4 migrating away from the cell nucleus, reducing the suppression of specific proteins. The researchers were intrigued to see if this phosphorylation of HDAC4 had any bearing on sleep.

“Our attention was primarily on a protein called salt-inducible kinase 3 (SIK3), which phosphorylates HDAC4,” Professor Funato details. “In earlier studies, we found this protein significantly influences sleep.” The team noted that sleep was diminished in the absence of SIK3 or when HDAC4 was altered to inhibit phosphorylation. Conversely, a more active variant of SIK3, enhancing the phosphorylation of HDAC4, led to a substantial increase in sleep. They also discovered another protein, LKB1, which phosphorylates SIK3, and similarly impacts sleep when deficient.

Co-senior author of the study, Professor Masashi Yanagisawa, explains their findings: “We discerned a signaling pathway within brain cells that extends from LKB1 to SIK3 and then to HDAC4. This pathway prompts the phosphorylation of HDAC4, which seemingly promotes sleep by influencing the expression of genes associated with sleep induction.”

The team performed additional experiments to pinpoint the specific brain cells where these pathways modulate sleep. They manipulated the levels of SIK3 and HDAC4 in various cell types and brain regions. Their findings suggested that cortical cell signaling controls sleep depth, whereas hypothalamic cell signaling determines the quantity of deep sleep. In both brain areas, the role of excitatory neurons, which activate other neurons, was found to be crucial.

These findings offer valuable insight into the regulatory mechanisms of sleep, paving the way towards a better comprehension of sleep disorders and the possibility of creating new therapeutic interventions.

Reference: “Kinase signalling in excitatory neurons regulates sleep quantity and depth” by Staci J. Kim, et al., 7 December 2022, Nature.
DOI: 10.1038/s41586-022-05450-1

This research was funded by the World Premier International Research Center Initiative from MEXT, JSPS KAKENHI, JST CREST, AMED, JSPS DC2, University of Tsukuba Basic Research Support Program Type A, and the Funding Program for World-Leading Innovative R&D on Science and Technology (FIRST Program).

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