TY - JOUR
T1 - Kinase signalling in excitatory neurons regulates sleep quantity and depth
AU - Kim, Staci J.
AU - Hotta-Hirashima, Noriko
AU - Asano, Fuyuki
AU - Kitazono, Tomohiro
AU - Iwasaki, Kanako
AU - Nakata, Shinya
AU - Komiya, Haruna
AU - Asama, Nodoka
AU - Matsuoka, Taeko
AU - Fujiyama, Tomoyuki
AU - Ikkyu, Aya
AU - Kakizaki, Miyo
AU - Kanno, Satomi
AU - Choi, Jinhwan
AU - Kumar, Deependra
AU - Tsukamoto, Takumi
AU - Elhosainy, Asmaa
AU - Mizuno, Seiya
AU - Miyazaki, Shinichi
AU - Tsuneoka, Yousuke
AU - Sugiyama, Fumihiro
AU - Takahashi, Satoru
AU - Hayashi, Yu
AU - Muratani, Masafumi
AU - Liu, Qinghua
AU - Miyoshi, Chika
AU - Yanagisawa, Masashi
AU - Funato, Hiromasa
N1 - Funding Information:
We thank all members of Yanagisawa/ Funato Lab and the International Institute for Integrative Sleep Medicine, especially K. Ebihara, M. Taniguchi, M. Sato for technical support, K. Iida, A. Kuno, M. Lazarus, E. Hasegawa, K. Roy, S. Wakana, T. Suzuki and I. Miura for technical advice and discussion, D. Kawaguchi for sharing Foxg1cremice, and E. Olson for sharing Hdac4floxmice. This work was supported by the World Premier International Research Center Initiative from MEXT to M.Y., JSPS KAKENHI (17H06095, 22H04918 to M.Y. and H.F.; 17H04023, 17H05583, 20H00567 to H.F.; 26507003, 18968064 to C.M. and H.F.; 15J00393, 18J21517 to F.A.; 18K14811 to T.F.; and 20J12137 to K.I.), JST CREST (JPMJCR1655 to M.Y.), AMED (JP21zf0127005 to M.Y.), JSPS DC2 (17J07957 to S.J.K.), the University of Tsukuba Basic Research Support Program Type A (to S.J.K.), and the Funding Program for World-Leading Innovative R&D on Science and Technology (FIRST Program) from JSPS (to M.Y.).
Funding Information:
We thank all members of Yanagisawa/ Funato Lab and the International Institute for Integrative Sleep Medicine, especially K. Ebihara, M. Taniguchi, M. Sato for technical support, K. Iida, A. Kuno, M. Lazarus, E. Hasegawa, K. Roy, S. Wakana, T. Suzuki and I. Miura for technical advice and discussion, D. Kawaguchi for sharing Foxg1 mice, and E. Olson for sharing Hdac4 mice. This work was supported by the World Premier International Research Center Initiative from MEXT to M.Y., JSPS KAKENHI (17H06095, 22H04918 to M.Y. and H.F.; 17H04023, 17H05583, 20H00567 to H.F.; 26507003, 18968064 to C.M. and H.F.; 15J00393, 18J21517 to F.A.; 18K14811 to T.F.; and 20J12137 to K.I.), JST CREST (JPMJCR1655 to M.Y.), AMED (JP21zf0127005 to M.Y.), JSPS DC2 (17J07957 to S.J.K.), the University of Tsukuba Basic Research Support Program Type A (to S.J.K.), and the Funding Program for World-Leading Innovative R&D on Science and Technology (FIRST Program) from JSPS (to M.Y.). cre flox
Publisher Copyright:
© 2022, The Author(s), under exclusive licence to Springer Nature Limited.
PY - 2022/12/15
Y1 - 2022/12/15
N2 - Progress has been made in the elucidation of sleep and wakefulness regulation at the neurocircuit level1,2. However, the intracellular signalling pathways that regulate sleep and the neuron groups in which these intracellular mechanisms work remain largely unknown. Here, using a forward genetics approach in mice, we identify histone deacetylase 4 (HDAC4) as a sleep-regulating molecule. Haploinsufficiency of Hdac4, a substrate of salt-inducible kinase 3 (SIK3)3, increased sleep. By contrast, mice that lacked SIK3 or its upstream kinase LKB1 in neurons or with a Hdac4S245A mutation that confers resistance to phosphorylation by SIK3 showed decreased sleep. These findings indicate that LKB1–SIK3–HDAC4 constitute a signalling cascade that regulates sleep and wakefulness. We also performed targeted manipulation of SIK3 and HDAC4 in specific neurons and brain regions. This showed that SIK3 signalling in excitatory neurons located in the cerebral cortex and the hypothalamus positively regulates EEG delta power during non-rapid eye movement sleep (NREMS) and NREMS amount, respectively. A subset of transcripts biased towards synaptic functions was commonly regulated in cortical glutamatergic neurons through the expression of a gain-of-function allele of Sik3 and through sleep deprivation. These findings suggest that NREMS quantity and depth are regulated by distinct groups of excitatory neurons through common intracellular signals. This study provides a basis for linking intracellular events and circuit-level mechanisms that control NREMS.
AB - Progress has been made in the elucidation of sleep and wakefulness regulation at the neurocircuit level1,2. However, the intracellular signalling pathways that regulate sleep and the neuron groups in which these intracellular mechanisms work remain largely unknown. Here, using a forward genetics approach in mice, we identify histone deacetylase 4 (HDAC4) as a sleep-regulating molecule. Haploinsufficiency of Hdac4, a substrate of salt-inducible kinase 3 (SIK3)3, increased sleep. By contrast, mice that lacked SIK3 or its upstream kinase LKB1 in neurons or with a Hdac4S245A mutation that confers resistance to phosphorylation by SIK3 showed decreased sleep. These findings indicate that LKB1–SIK3–HDAC4 constitute a signalling cascade that regulates sleep and wakefulness. We also performed targeted manipulation of SIK3 and HDAC4 in specific neurons and brain regions. This showed that SIK3 signalling in excitatory neurons located in the cerebral cortex and the hypothalamus positively regulates EEG delta power during non-rapid eye movement sleep (NREMS) and NREMS amount, respectively. A subset of transcripts biased towards synaptic functions was commonly regulated in cortical glutamatergic neurons through the expression of a gain-of-function allele of Sik3 and through sleep deprivation. These findings suggest that NREMS quantity and depth are regulated by distinct groups of excitatory neurons through common intracellular signals. This study provides a basis for linking intracellular events and circuit-level mechanisms that control NREMS.
UR - http://www.scopus.com/inward/record.url?scp=85143410407&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85143410407&partnerID=8YFLogxK
U2 - 10.1038/s41586-022-05450-1
DO - 10.1038/s41586-022-05450-1
M3 - Article
C2 - 36477539
AN - SCOPUS:85143410407
SN - 0028-0836
VL - 612
SP - 512
EP - 518
JO - Nature
JF - Nature
IS - 7940
ER -