Constructing the suprachiasmatic nucleus: a watchmaker's perspective on the central clockworks

Bedont, Joseph L.; Blackshaw, Seth

doi:10.3389/fnsys.2015.00074

Cited by 75 publications

(61 citation statements)

References 270 publications

(421 reference statements)

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“…This postnatal maturation of this SCN network likely involves synaptogenesis which begins around P2 when we found the onset of the phase wave (Bedont and Blackshaw, 2015). It will be intriguing to map the synaptic network topology that contributes to the phase relationships among SCN cells (Abel et al, 2016;Buijink et al, 2016).…”

Section: Discussionmentioning

confidence: 83%

Ontogeny of Circadian Rhythms and Synchrony in the Suprachiasmatic Nucleus

et al. 2017

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In mammals, the suprachiasmatic nucleus (SCN) of the hypothalamus coordinates daily rhythms including sleep-wake, hormone release and gene expression. The cells of the SCN must synchronize to each other to drive these circadian rhythms in the rest of the body. The ontogeny of circadian cycling and intercellular coupling in the SCN remains poorly understood. Recent in vitro studies have recorded circadian rhythms from the whole embryonic SCN. Here, we tracked the onset and precision of rhythms in PERIOD2 (PER2), a clock protein, within the SCN isolated from embryonic and postnatal mice of undetermined sex. We found that a few SCN cells developed circadian periodicity in PER2 by 14.5 days after mating (E14.5) with no evidence for daily cycling on E13.5. On E15.5, the fraction of competent oscillators increased dramatically corresponding with stabilization of their circadian periods. The cells of the SCN harvested at E15.5 expressed sustained, synchronous daily rhythms. By postnatal day 2 (P2), SCN oscillators displayed the daily, dorsal-ventral phase wave in clock gene expression typical of the adult SCN.Strikingly, vasoactive intestinal polypeptide (VIP), a neuropeptide critical for synchrony in the adult SCN, and its receptor, VPAC2R, reached detectable levels after birth and after the onset of circadian synchrony. Antagonists of GABA or VIP signaling or action potentials did not disrupt circadian synchrony in the E15.5 SCN. We conclude that endogenous daily rhythms in the fetal SCN begin with few noisy oscillators on E14.5, followed by widespread oscillations that rapidly synchronize on E15.5 by an unknown mechanism. 2 Significance StatementWe recorded the onset of PER2 circadian oscillations during embryonic development in the mouse SCN. When isolated at E13.5, the anlagen of the SCN expresses high, arrhythmic PER2. In contrast, a few cells show noisy circadian rhythms in the isolated E14.5 SCN and most show reliable, self-sustained, synchronized rhythms in the E15.5 SCN. Strikingly, this synchrony at E15.5 appears prior to expression of VIP or its receptor and persists in the presence of blockers of VIP, GABA or neuronal firing. Finally, the dorsal-ventral phase wave of PER2 typical of the adult SCN appears around P2, indicating that multiple signals may mediate circadian synchrony during the ontogeny of the SCN.

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Section: Discussionmentioning

confidence: 83%

Ontogeny of Circadian Rhythms and Synchrony in the Suprachiasmatic Nucleus

et al. 2017

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“…Collectively, these results support the view that the anterior and posterior SCN are distinct compartments (Figure 13). Together with accumulating evidence of other structural and functional differences along the anteroposterior axis of the SCN (Bedont & Blackshaw, 2015;Evans et al, 2011;Inagaki et al, 2007;Lokshin et al, 2015;Morin, 2007) this leads us to postulate the existence of discrete anterior and posterior SCN subdomains, oriented orthogonally to and overlapping the classical core/shell axis of the network.…”

Section: Anterior and Posterior Scn Are Neurochemically And Functiomentioning

confidence: 83%

Asymmetric vasopressin signaling spatially organizes the master circadian clock

Bedont

Rohr

Bathini

et al. 2018

J of Comparative Neurology

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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.

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“…However, retrograde tracing experiments from the SCN revealed that some SCN-projecting M1 cells were Rasgrp1-immunonegative. Accumulating research suggests that the SCN is more compartmentalized than previously recognized (Bedont and Blackshaw, 2015). The question of whether Rasgrp1 is expressed in a subset of M1 ipRGCs that targets a specific compartment of the SCN remains to be determined.…”

Section: Discussionmentioning

confidence: 99%

Molecular Diversity of Intrinsically Photosensitive Ganglion Cells

Berg

Leyrer

et al. 2018

Preprint

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14Intrinsically photosensitive retinal ganglion cells (ipRGCs) are rare mammalian photoreceptors 15 essential for non-image-forming vision functions, such as circadian photoentrainment and the 16 pupillary light reflex. They comprise multiple subtypes distinguishable by morphology, physiology, 17 projections, and levels of expression of melanopsin (Opn4), their photopigment. The molecular 18 programs that differentiate ipRGCs from other ganglion cells and ipRGC subtypes from one 19 another remain elusive. Here, we present comprehensive gene expression profiles of early 20 postnatal and adult mouse ipRGCs purified from two lines of reporter mice marking different sets 21 of ipRGC subtypes. We find dozens of novel genes highly enriched in ipRGCs. We reveal that 22 Rasgrp1 and Tbx20 are selectively expressed in subsets of ipRGCs, though these molecularly 23 defined groups imperfectly match established ipRGC subtypes. We demonstrate that the ipRGCs 24 regulating circadian photoentrainment are unexpectedly diverse at the molecular level. Our 25 findings reveal unexpected complexity in gene expression patterns across mammalian ipRGC 26 subtypes.

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Constructing the suprachiasmatic nucleus: a watchmaker's perspective on the central clockworks

Cited by 75 publications

References 270 publications

Ontogeny of Circadian Rhythms and Synchrony in the Suprachiasmatic Nucleus

Ontogeny of Circadian Rhythms and Synchrony in the Suprachiasmatic Nucleus

Asymmetric vasopressin signaling spatially organizes the master circadian clock

Molecular Diversity of Intrinsically Photosensitive Ganglion Cells

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