小柯机器人

日本筑波大学Hiromasa Funato等研究人员合作发现，兴奋性神经元的激酶信号调节睡眠数量和深度。该研究于2022年12月7日在线发表于国际一流学术期刊《自然》。

通过利用小鼠的正向遗传学方法，研究人员确定组蛋白去乙酰化酶4（HDAC4）是一种调节睡眠的分子。Hdac4是盐诱导激酶3（SIK3）的底物，Hdac4的单倍性不足增加了睡眠。相反，在神经元中缺乏SIK3或其上游激酶LKB1的小鼠，或具有Hdac4^S245A突变的小鼠，其对SIK3的磷酸化具有抵抗力，显示出睡眠减少。这些发现表明，LKB1-SIK3-HDAC4构成了一个调节睡眠和觉醒的信号级联。研究人员还在特定的神经元和脑区对SIK3和HDAC4进行了定向操作。

这表明，位于大脑皮层和下丘脑的兴奋性神经元中的SIK3信号分别在非快速眼动睡眠（NREMS）和NREMS量期间积极地调节EEG delta功率。通过Sik3的功能增益等位基因的表达和睡眠剥夺，大脑皮层谷氨酸神经元中偏向于突触功能的转录物亚群被普遍调节。这些发现表明，NREMS的数量和深度是由不同的兴奋性神经元群体通过共同的细胞内信号进行调节。这项研究为将控制NREMS的细胞内事件和回路级机制联系起来提供了一个基础。

据悉，在神经回路水平上对睡眠和觉醒调节的阐释已经取得了进展。然而，调节睡眠的细胞内信号通路和这些细胞内机制发挥作用的神经元组在很大程度上仍然是未知的。

附：英文原文

Title: Kinase signalling in excitatory neurons regulates sleep quantity and depth

Author: Kim, Staci J., Hotta-Hirashima, Noriko, Asano, Fuyuki, Kitazono, Tomohiro, Iwasaki, Kanako, Nakata, Shinya, Komiya, Haruna, Asama, Nodoka, Matsuoka, Taeko, Fujiyama, Tomoyuki, Ikkyu, Aya, Kakizaki, Miyo, Kanno, Satomi, Choi, Jinhwan, Kumar, Deependra, Tsukamoto, Takumi, Elhosainy, Asmaa, Mizuno, Seiya, Miyazaki, Shinichi, Tsuneoka, Yousuke, Sugiyama, Fumihiro, Takahashi, Satoru, Hayashi, Yu, Muratani, Masafumi, Liu, Qinghua, Miyoshi, Chika, Yanagisawa, Masashi, Funato, Hiromasa

Issue&Volume: 2022-12-07

Abstract: 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 deacetylase4 (HDAC4) as a sleep-regulating molecule. Haploinsufficiency of Hdac4, a substrate of salt-inducible kinase3 (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.

DOI: 10.1038/s41586-022-05450-1

Source: https://www.nature.com/articles/s41586-022-05450-1

Nature：《自然》，创刊于1869年。隶属于施普林格·自然出版集团，最新IF：69.504
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