Division of Neurobiology, MRC Laboratory of Molecular Biology, Cambridge, UK.
The Genome Editing Unit, Faculty of Biology, Medicine and Health, University of Manchester, Manchester, UK.
EMBO J. 2021 Oct 18;40(20):e108614. doi: 10.15252/embj.2021108614. Epub 2021 Sep 6.
Circadian rhythms in mammals are governed by the hypothalamic suprachiasmatic nucleus (SCN), in which 20,000 clock cells are connected together into a powerful time-keeping network. In the absence of network-level cellular interactions, the SCN fails as a clock. The topology and specific roles of its distinct cell populations (nodes) that direct network functions are, however, not understood. To characterise its component cells and network structure, we conducted single-cell sequencing of SCN organotypic slices and identified eleven distinct neuronal sub-populations across circadian day and night. We defined neuropeptidergic signalling axes between these nodes, and built neuropeptide-specific network topologies. This revealed their temporal plasticity, being up-regulated in circadian day. Through intersectional genetics and real-time imaging, we interrogated the contribution of the Prok2-ProkR2 neuropeptidergic axis to network-wide time-keeping. We showed that Prok2-ProkR2 signalling acts as a key regulator of SCN period and rhythmicity and contributes to defining the network-level properties that underpin robust circadian co-ordination. These results highlight the diverse and distinct contributions of neuropeptide-modulated communication of temporal information across the SCN.
哺乳动物的昼夜节律受下丘脑视交叉上核（SCN）的控制，其中 20000 个时钟细胞连接在一起，形成一个强大的计时网络。如果没有网络级别的细胞相互作用，SCN 就无法作为时钟发挥作用。然而，其指导网络功能的不同细胞群体（节点）的拓扑结构和特定作用尚不清楚。为了描述其组成细胞和网络结构，我们对 SCN 器官型切片进行了单细胞测序，在昼夜节律的白天和黑夜中鉴定出了 11 种不同的神经元亚群。我们定义了这些节点之间的神经肽信号轴，并构建了神经肽特异性网络拓扑结构。这揭示了它们的时间可塑性，在昼夜节律的白天上调。通过交差遗传和实时成像，我们研究了 Prok2-ProkR2 神经肽轴对网络范围计时的贡献。我们表明，Prok2-ProkR2 信号作为 SCN 周期和节律的关键调节剂发挥作用，并有助于定义支持稳健的昼夜协调的网络级特性。这些结果突出了 SCN 中跨时信息的神经肽调节通讯的多样性和独特性贡献。
