Abstract
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.
Highlights
The ca. 20,000 circadian clock cells of the mammalian suprachiasmatic nucleus (SCN) (Abrahamson & Moore, 2001) coordinate sub-ordinate cellular clocks distributed across the body and, Alastair Crisp1, Antony Adamson2 thereby sustain adaptive daily rhythms of physiology and behaviour (Reppert & Weaver, 2002)
Individual cells maintain near 24 h autonomous rhythms through self-sustaining transcriptional/ translational feedback loops (TTFLs) (Partch et al, 2014), whereby Period (Per) and Cryptochrome (Cry) proteins negatively regulate their own expression, which is trans-activated by CLOCK:BMAL1 heterodimers
We revealed that the neuropeptidergic signalling axis based on cells expressing Prokineticin2 (Prok2) and its cognate receptor (ProkR2) is a transcriptionally, topologically and functionally distinct pacemaking element of the SCN
Summary
The ca. 20,000 circadian (circa-diem) clock cells of the mammalian suprachiasmatic nucleus (SCN) (Abrahamson & Moore, 2001) coordinate sub-ordinate cellular clocks distributed across the body and, Alastair Crisp, Antony Adamson thereby sustain adaptive daily rhythms of physiology and behaviour (Reppert & Weaver, 2002). Individual cells maintain near 24 h autonomous rhythms through self-sustaining transcriptional/ translational feedback loops (TTFLs) (Partch et al, 2014), whereby Period (Per) and Cryptochrome (Cry) proteins negatively regulate their own expression, which is trans-activated by CLOCK:BMAL1 heterodimers These cellular TTFLs are coupled and synchronised across the SCN by paracrine and synaptic signals (Yamaguchi et al, 2003; Maywood et al, 2011; Noguchi et al, 2017; Patton et al, 2020). Conditional activation of the TTFL of SCN neurons alone initiates circadian rhythms in the SCN, but is sufficient to drive circadian behaviour in an otherwise clockless mouse (Maywood et al, 2018) This powerful autonomous time-keeping of the SCN is evident in its ability to maintain precise network-level rhythmicity when isolated in vitro (Green & Gillette, 1982; Yamaguchi et al, 2003). The cellular, neurochemical and topological bases of the network mechanisms that generate such a reliable oscillator remain unclear
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
