Shell neurons of the master circadian clock coordinate the phase of tissue clocks throughout the brain and body

Abstract

BackgroundDaily rhythms in mammals are programmed by a master clock in the suprachiasmatic nucleus (SCN). The SCN contains two main compartments (shell and core), but the role of each region in system-level coordination remains ill defined. Herein, we use a functional assay to investigate how downstream tissues interpret region-specific outputs by using in vivo exposure to long day photoperiods to temporally dissociate the SCN. We then analyze resulting changes in the rhythms of clocks located throughout the brain and body to examine whether they maintain phase synchrony with the SCN shell or core.ResultsNearly all of the 17 tissues examined in the brain and body maintain phase synchrony with the SCN shell, but not the SCN core, which indicates that downstream oscillators are set by cues controlled specifically by the SCN shell. Interestingly, we also found that SCN dissociation diminished the amplitude of rhythms in core clock gene and protein expression in brain tissues by 50–75 %, which suggests that light-driven changes in the functional organization of the SCN markedly influence the strength of rhythms in downstream tissues.ConclusionsOverall, our results reveal that body clocks receive time-of-day cues specifically from the SCN shell, which may be an adaptive design principle that serves to maintain system-level phase relationships in a changing environment. Further, we demonstrate that lighting conditions alter the amplitude of the molecular clock in downstream tissues, which uncovers a new form of plasticity that may contribute to seasonal changes in physiology and behavior.Electronic supplementary materialThe online version of this article (doi:10.1186/s12915-015-0157-x) contains supplementary material, which is available to authorized users.

Functional network inference of the suprachiasmatic nucleus

“…Prominent modeling studies of the past decade have assumed a wide variety of network structures: nearest neighbor (15,20), small-world (21), or mean-field (22,23), or combinations of these depending on coupling pathway (16), pointing to the high degree of uncertainty regarding the general connectivity of the SCN. There has been significant recent interest in attempting to elucidate the network structure and mechanisms driving synchrony the SCN, commonly through light-driven desynchronization assays (19,(24)(25)(26). These methods have the advantage of reducing the SCN into large phase clusters of neurons, whose behavior can be easily tracked and modeled with reduced approaches (26).…”

Collective timekeeping among cells of the master circadian clock

“…In addition to its ecological significance, plasticity in SCN phase relationships can be exploited to test mechanisms of intercellular communication (Evans et al 2013; Evans, et al 2015). In this approach, SCN neurons are desynchronized by light in vivo and then allowed to re-synchronize in vitro so that the process of network coupling can be tracked in real time.…”

“…The functional roles of projections from distinct SCN regions are far from fully understood. Thus far, research indicates that both SCN compartments influence rhythms in downstream targets, yet there are differences in the role of outputs from different SCN regions (Butler, et al 2012; Evans et al 2015; Kalsbeek, et al 2010; Lee, et al 2009; Schwartz, et al 2009; Smarr, et al 2012; Wotus, et al 2013; Yan, et al 2005; Zhou and Cheng 2005). One emerging theme is that the SCN shell appears to set the phase of downstream tissues; however, both SCN shell and core neurons provide signals to downstream tissues that can influence their rhythms.…”

In synch but not in step: Circadian clock circuits regulating plasticity in daily rhythms

“…The current working model of photic signaling is that the SCN core contains first order neurons that receive afferent input, which process and transmit this information to neurons in the SCN shell. On the other hand, the SCN shell is thought to contain strongly rhythmic cells that provide outputs to reset the phase of downstream tissues (Nakamura et al, 2001, Dardente et al, 2002, Zhou and Cheng, 2005, Kalsbeek et al, 2010, Evans et al, 2015). However, there are aspects of this model that remain unclear.…”