期刊：Nature
发表时间：2022/12/07
数字识别码：10.1038/s41586-022-05450-1
摘要：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.
所属学科：
神经科学
撰文 | 亦
近年来，睡眠和觉醒的调控在神经环路水平的阐释取得了很大进步【1,2】，一些神经元群体被报道参与睡眠稳态调控【3-5】，但负责调控的细胞信号通路和参与的神经元群体很大程度上还不为人知。SIK3是睡眠稳态调节中关键的组分，它在神经元中的表达会增加睡眠数量，导致非快速眼动睡眠（non-rapid eye movement sleep, NREMS）期的脑电图（electroencephalogram, EEG）δ电流增强【6】，它的剪切突变Sik3也会有类似效果，其残基S551对于睡眠增加也很关键，但这一通路的上下游分子途径还有待阐明。
2022年12月7日，来自日本筑波大学国际综合睡眠医学研究所的Masashi Yanagisawa和Hiromasa Funato在Nature上发表了题为Kinase signalling in excitatory neurons regulates sleep quantity and depth的文章，鉴定出了睡眠调控分子——组蛋白酶脱乙酰酶4（HDAC4）和调节睡眠及觉醒状态的信号级联LKB1–SIK3–HDAC4，揭示了大脑皮层和下丘脑兴奋性神经元中SIK3信号通路在NREMS期的调节作用（另一篇背靠背的类似工作详见：Nature背靠背｜刘清华等揭开睡眠量转录调控之谜）。
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