The cell-autonomous clock of VIP receptor VPAC2 cells drives circadian behaviour
The cell-autonomous clock of VIP receptor VPAC2 cells drives circadian behaviour
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DOI：
10.1101/2020.08.02.232462
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发表时间：
2020-08
期刊：
影响因子：
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通讯作者：
R. Hamnett;J. Chesham;E. Maywood;M. Hastings
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文献类型：
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作者：
R. Hamnett;J. Chesham;E. Maywood;M. Hastings
哺乳动物的行为都有昼夜节律。它们是由细胞自主的转录/翻译反馈环（TTFL）产生的，在所有组织中都有活性。这种分布式时钟网络是由主要的昼夜节律起搏器，下丘脑视交叉上核（SCN）协调。其强大而准确的时间保持来自电路级的相互作用，将其各个细胞时钟绑定到一个连贯的时间保持器中。表达神经肽血管活性肠肽（VIP）的细胞介导SCN的视网膜夹带，并且在不存在VIP或其同源受体VPAC 2的情况下，昼夜节律行为受到损害，因为SCN细胞不能同步。然而，对SCN起搏和其他细胞类型的昼夜节律行为的贡献，尤其是VIP的VPAC 2表达靶细胞，还不清楚。因此，我们采用交叉遗传学来操纵VPAC 2表达细胞的细胞自主TTFL，从而产生时间嵌合小鼠。然后，我们可以确定表达VPAC 2的细胞（占SCN细胞的约35%）是否以及如何有助于SCN的计时。通过删除CK 1 εTau等位基因延长VPAC 2细胞的固有TTFL周期，同时延长了昼夜行为节律的周期。它还增加了离体记录的SCN切片中生物发光TTFL节律的昼夜节律周期的可变性。通过删除Bmal 1来消除VPAC 2细胞中的昼夜节律能力严重破坏了昼夜节律行为节律，并损害了相应SCN切片中的TTFL时间保持。因此，表达VPAC 2的细胞是SCN回路的独特的、功能强大的子集，有助于计算集合周期和维持昼夜节律的稳健性。这些发现扩展了我们对SCN电路拓扑结构的理解。
Circadian (∼daily) rhythms pervade mammalian behaviour. They are generated by cell-autonomous, transcriptional/translational feedback loops (TTFL), active in all tissues. This distributed clock network is co-ordinated by the principal circadian pacemaker, the hypothalamic suprachiasmatic nucleus (SCN). Its robust and accurate time-keeping arises from circuit-level interactions that bind its individual cellular clocks into a coherent time-keeper. Cells that express the neuropeptide vasoactive intestinal peptide (VIP) mediate retinal entrainment of the SCN, and in the absence of VIP, or its cognate receptor VPAC2, circadian behaviour is compromised because SCN cells cannot synchronise. The contributions to SCN pacemaking and circadian behaviour of other cell types, not least the VPAC2-expressing target cells of VIP, are, however, not understood. We therefore employed intersectional genetics to manipulate the cell-autonomous TTFL of VPAC2-expressing cells, creating temporally chimaeric mice. We could then determine whether and how VPAC2-expressing cells (a minority ∼35% of SCN cells) contribute to SCN time-keeping. Lengthening of the intrinsic TTFL period of VPAC2 cells by deletion of the CK1εTau allele concomitantly lengthened the period of circadian behavioural rhythms. It also increased the variability of the circadian period of bioluminescent TTFL rhythms in SCN slices recorded ex vivo. Abrogation of circadian competence in VPAC2 cells by deletion of Bmal1 severely disrupted circadian behavioural rhythms and compromised TTFL time-keeping in the corresponding SCN slices. Thus, VPAC2-expressing cells are a distinct, functionally powerful subset of the SCN circuit, contributing to computation of ensemble period and maintenance of circadian robustness. These findings extend our understanding of SCN circuit topology.