Asymmetric vasopressin signaling spatially organizes the master circadian clock

Abstract

The suprachiasmatic nucleus (SCN) is the neural network that drives daily rhythms in behavior and physiology. The SCN encodes environmental changes through the phasing of cellular rhythms across its anteroposterior axis, but it remains unknown what signaling mechanisms regulate clock function along this axis. Here we demonstrate that arginine vasopressin (AVP) signaling organizes the SCN into distinct anteroposterior domains. Spatial mapping of SCN gene expression using in situ hybridization delineated anterior and posterior domains for AVP signaling components, including complementary patterns of V1a and V1b expression that suggest different roles for these two AVP receptors. Similarly, anteroposterior patterning of transcripts involved in Vasoactive Intestinal Polypeptide- and Prokineticin2 signaling was evident across the SCN. Using bioluminescence imaging, we then revealed that inhibiting V1A and V1B signaling alters period and phase differentially along the anteroposterior SCN. V1 antagonism lengthened period the most in the anterior SCN, whereas changes in phase were largest in the posterior SCN. Further, separately antagonizing V1A and V1B signaling modulated SCN function in a manner that mapped onto anteroposterior expression patterns. Lastly, V1 antagonism influenced SCN period and phase along the dorsoventral axis, complementing effects on the anteroposterior axis. Together, these results indicate that AVP signaling modulates SCN period and phase in a spatially specific manner, which is expected to influence how the master clock interacts with downstream tissues and responds to environmental changes. More generally, we reveal anteroposterior asymmetry in neuropeptide signaling as a recurrent organizational motif that likely influences neural computations in the SCN clock network.

The VIP-VPAC2 neuropeptidergic axis is a cellular pacemaking hub of the suprachiasmatic nucleus circadian circuit

“…Recent single-cell SCN transcriptomic analysis has identified putative topological elements involving peptides (AVP, Prok2, PACAP, and VIP) and their cognate receptors 18 that mediate paracrine and/or autocrine signalling 29,30 . Through direct experimental manipulation, we now show that one of these molecularly defined elements, the VIP/VPAC2 cellular axis, consists of serially active topological components of the SCN circuit and determines circuit-level emergent properties of the network.…”

Circuit development in the master clock network of mammals

“…Interestingly, VIP signalling does not appear to be required for SCN synchrony at E15.5 (Carmona‐Alcocer et al., ; Wreschnig et al., ), suggesting that other signalling mechanisms support network function at this age. The loss of VIP signalling reduces the expression of other SCN neuropeptides in adulthood, such as Avp and Prok2 (Bedont et al., ; Harmar et al, ; Bedont et al, ), which could reflect loss of SCN synchrony during adulthood or a developmental deficit in network maturation. With this in mind, it may be interesting to examine whether levels of these other neuropeptides are rescued by treatments that restore intercellular synchrony in VIP‐deficient SCN (Aton et al., ; Brown, et al, ; Hughes et al., ; Maywood et al., ).…”

“…Recent work indicates that signalling by AVP neurons regulates SCN function in ways beyond its role as an output to downstream tissues (Kalsbeek, Fliers, Hofman, Swaab & Buijs, ). The SCN expresses transcripts for the AVP receptors, V1a and V1b (Bedont, et al, ), and inhibition of AVP signalling modulates SCN rhythms in vitro by affecting the period and phase relationships of SCN neurons (Bedont et al., ; Edwards, Brancaccio, Chesham, Maywood & Hastings, ). In vivo, deletion of V1a/b receptors accelerates behavioural and molecular recovery from simulated jetlag, which is mimicked by injections of V1A and V1B antagonists into the SCN (Yamaguchi, et al, ).…”

Synchronization and maintenance of circadian timing in the mammalian clockwork

“…Using a co‐culture paradigm both VIP and VIP‐independent pathways, including AVP and GRP, were identified as paracrine inter‐neuronal signals that can drive coherent circadian rhythmicity and compensate for the genetic deficiency ( Cry1,2 knockout slices) of SCN neurons (Maywood, Chesham, O'Brien, & Hastings, ). Furthermore, AVP may be important in maintaining the regional antero‐posterior phase differences across the SCN circuitry (Bedont et al., ). Having identified AVP as a putative modulator of circuit‐based properties, the authors proposed a model where AVP and VIP could act together to organise the circuit along the anterior‐posterior and dorso‐ventral axes of the SCN (Bedont et al., ).…”

“…Furthermore, AVP may be important in maintaining the regional antero‐posterior phase differences across the SCN circuitry (Bedont et al., ). Having identified AVP as a putative modulator of circuit‐based properties, the authors proposed a model where AVP and VIP could act together to organise the circuit along the anterior‐posterior and dorso‐ventral axes of the SCN (Bedont et al., ). Whereas, the majority of SCN neurons express GABA, its role in neuronal coupling is less clear.…”