Progress has been made in elucidating sleep and wake regulation at the neurocircuitry level. However, the intracellular signaling pathways regulating sleep and the neuron groups in which these intracellular mechanisms operate remain largely unknown.

A new study by scientists at the University of Tsukuba used a forward genetic approach in mice and revealed a signaling pathway in brain cells that regulates the length and depth of sleep.

In particular, they examined genetic mutations in mice and how they affect their sleep patterns. They then identified a mutation that caused the mice to sleep much longer and more deeply than usual.

Low levels of the enzyme histone deacetylase 4 (HDAC4), known to limit expression of target genes, appeared to be the cause, the scientists found.

Senior author of the study, Professor Hiromasa Funato, said: “We focused on a protein called salt-inducible kinase 3, also known as SIK3, which phosphorylates HDAC4. We previously discovered that this protein has strong effects on sleep.”

The scientists found that the mice slept less when SIK3 was absent or when HDAC4 was altered to inhibit phosphorylation. The mice slept significantly more when they had a more active form of SIK3, which increased HDAC4 phosphorylation. They also discovered another protein, LKB1, which phosphorylates SIK3 and, when it is missing, has similar sleep-inhibiting effects.

Study co-senior author Professor Masashi Yanagisawa said: “Our findings point to a signaling pathway in brain cells from LKB1 to SIK3 and then to HDAC4. This pathway leads to the phosphorylation of HDAC4, which promotes sleep, most likely because it affects the expression of sleep-promoting genes.”

Scientists did further research to determine which brain cells in these networks control sleep. This required altering the concentrations of SIK3 and HDAC4 in different brain cell types and parts. The findings showed that signaling in the hypothalamus controls the amount of deep sleep and signaling in the cortical cells controls the depth of sleep. The excitatory neurons, which can stimulate other neurons, turned out to be crucial in both brain regions.

These results provide vital insight into how sleep is regulated, potentially leading to a better understanding of sleep disorders and the development of new treatments.

Magazine reference:

  1. Kim, SJ, Hotta-Hirashima, N., Asano, F. et al. Kinase signaling in excitatory neurons regulates sleep amount and depth. Nature 612, 512-518 (2022). DOI: 10.1038/s41586-022-05450-1