Kinase signalling in excitatory neurons regulates sleep quantity and depth
Kinase signalling in excitatory neurons regulates sleep quantity and depth
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DOI：
10.1038/s41586-022-05450-1
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发表时间：
2022-12-07
期刊：
影响因子：
64.8
通讯作者：
Funato，Hiromasa
中科院分区：
文献类型：
--
作者：
Kim，Staci J.;Hotta-Hirashima，Noriko;Funato，Hiromasa
在神经回路水平上对睡眠和觉醒调节的阐明已经取得了进展。然而，调节睡眠的细胞内信号传导途径以及这些细胞内机制工作的神经元群在很大程度上仍然未知。在这里，使用小鼠的正向遗传学方法，我们确定组蛋白去乙酰化酶4（HDAC 4）作为睡眠调节分子。盐诱导激酶3（SIK 3）的底物Hdac 4的单倍不足增加了睡眠。相比之下，神经元中缺乏SIK 3或其上游激酶LKB 1或具有aHdac 4S 245 A突变的小鼠表现出对SIK 3磷酸化的抗性，睡眠减少。这些发现表明LKB 1-SIK 3-HDAC 4构成了调节睡眠和觉醒的信号级联反应。我们还在特定的神经元和大脑区域进行了SIK 3和HDAC 4的靶向操作。这表明位于大脑皮层和下丘脑中的兴奋性神经元中的SIK 3信号传导分别在非快速眼动睡眠（NREMS）和NREMS量期间正向调节EEG δ功率。一个子集的成绩单偏向于突触功能的调节通常在皮层神经元通过表达的功能获得等位基因的Sik 3和通过睡眠剥夺。这些结果表明，NREMS的数量和深度调节不同群体的兴奋性神经元通过共同的细胞内信号。这项研究为连接细胞内事件和控制NREMS的回路水平机制提供了基础。
Progress has been made in the elucidation of sleep and wakefulness regulation at the neurocircuit level,. 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 ofHdac4, a substrate of salt-inducible kinase 3 (SIK3), increased sleep. By contrast, mice that lacked SIK3 or its upstream kinase LKB1 in neurons or with aHdac4S245Amutation 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 ofSik3and 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.