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Regulating the Suprachiasmatic Nucleus (SCN) Circadian Clockwork: Interplay Between Cell- Autonomous and Circuit-Level Mechanisms

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Regulating the Suprachiasmatic Nucleus (SCN) Circadian Clockwork: Interplay Between Cell- Autonomous and Circuit-Level Mechanisms Downloaded from http://cshperspectives.cshlp.org/ on October 8, 2021 - Published by Cold Spring Harbor Laboratory Press Regulating the Suprachiasmatic Nucleus (SCN) Circadian Clockwork: Interplay between Cell- Autonomous and Circuit-Level Mechanisms Erik D. Herzog,1 Tracey Hermanstyne,1 Nicola J. Smyllie,2 and Michael H. Hastings2 1Department of Biology, Washington University in St. Louis, St. Louis, Missouri 63130-4899 2Division of Neurobiology, MRC Laboratory of Molecular Biology, Cambridge CB2 0QH, United Kingdom Correspondence: [email protected]; [email protected] The suprachiasmatic nucleus (SCN) is the principal circadian clock of the brain, directing daily cycles of behavior and physiology. SCN neurons contain a cell-autonomous transcrip- tion-based clockwork but, in turn, circuit-level interactions synchronize the 20,000 or so SCN neurons into a robust and coherent daily timer. Synchronization requires neuropeptide signaling, regulated by a reciprocal interdependence between the molecular clockwork and rhythmic electrical activity, which in turn depends on a daytime Naþ drive and nighttime Kþ drag. Recent studies exploiting intersectional genetics have started to identify the pacemak- ing roles of particular neuronal groups in the SCN. They support the idea that timekeeping involves nonlinear and hierarchical computations that create and incorporate timing infor- mation through the interactions between key groups of neurons within the SCN circuit. The field is now poised to elucidate these computations, their underlying cellular mechanisms, and how the SCN clock interacts with subordinate circadian clocks across the brain to determine the timing and efficiency of the sleep–wake cycle, and how perturbations of this coherence contribute to neurological and psychiatric illness. e wake and sleep each day. Hormones ation of circadian time, and how cells within the Wreach peak plasma levels at specified SCN synchronize their daily rhythms across the times, for example cortisol peaks in the early circuit to produce a coherent oscillation in neu- morning. These, and many other physiological ronal activity. It is these circuit-level emergent and behavioral, daily rhythms depend on an properties of the SCN that ultimately direct internal circadian clock, the suprachiasmatic daily behaviors such as wake and sleep. nucleus (SCN) of the hypothalamus. Prior re- views have provided excellent summaries of re- A BRIEF TIMELINE OF THE SCN CLOCK search progress in the location and function of this body clock (Weaver 1998). This work fo- The SCN is the principal circadian pacemaker in cuses on recent advances in our understanding mammals, autonomously capable of defining of the genetic basis for cell-autonomous gener- temporal cycles with a period of 24 hours, Editors: Paolo Sassone-Corsi, Michael W. Young, and Akhilesh B. Reddy Additional Perspectives on Circadian Rhythms available at www.cshperspectives.org Copyright # 2017 Cold Spring Harbor Laboratory Press; all rights reserved; doi: 10.1101/cshperspect.a027706 Cite this article as Cold Spring Harb Perspect Biol 2017;9:a027706 1 Downloaded from http://cshperspectives.cshlp.org/ on October 8, 2021 - Published by Cold Spring Harbor Laboratory Press E.D. Herzog et al. and are necessary for the expression of coherent disconnected from the rest of the brain. The daily rhythms of physiology, behavior, and me- SCN, therefore, is a tissue-based clock. The po- tabolism in the intact animal (Fig. 1). The prin- tency of this clock function was shown by intra- cipal discoveries regarding the clock function of cerebral grafting, in vivo, of fetal SCN into the the SCN are reviewed extensively elsewhere brain of rodents carrying SCN lesions. These (Weaver 1998), but the key observations are as grafts restored circadian patterning to the ar- follows. Although ablation studies had indicat- rhythmic activity/rest behaviors, with a period ed a hypothalamic site for the circadian clock, determined by the genotype of the grafted tis- the SCN only came to attention once autoradio- sue. This showed, definitively, that the SCN was graphic tracing methods revealed it as a site of necessary and sufficient to sustain circadian be- retinal innervation, the principal termination haviors. The cell-autonomous nature of time- site of the retinohypothalamic tract (RHT). keeping was shown in dispersed cultures of Subsequent lesion studies showed that behav- SCN, in which the spontaneous electrical activ- ioral, endocrine, and seasonal rhythms were ity of individual neurons was circadian but free- compromised when the SCN was damaged. Au- ran independent of other neurons in the same toradiographic metabolic imaging and electro- culture. Indeed, fully isolated SCN neurons can physiological studies showed that activity in the express daily rhythms in repetitive firing rates SCN is rhythmic in vivo. In addition, slice elec- and gene expression (Webbet al. 2009). Circuit- trophysiology showed that the electrical circadi- level properties of the SCN are nevertheless im- an rhythms were sustained in vitro, even when portant; the ventrolateral (core) and dorso- A B C 30 25 20 15 Isolated 10 Bioluminescence (counts) 5 0 24 48 72 96 120 144 168 192 216 240 Time (h) Figure 1. Isolated neurons of the suprachiasmatic nucleus (SCN) are competent, cell-autonomous circadian pacemakers. (A,B) Micrographs of cultured SCN neurons before A, and after B, physically isolating a single neuron (arrow). Scale bars, 50 mm. (C) Recording of PER2 expression using a bioluminescent reporter of PER2 abundance reveals persistent daily rhythms before and after the neuron was isolated. (From Webb et al. 2009; reproduced, with permission, from the authors.) 2 Cite this article as Cold Spring Harb Perspect Biol 2017;9:a027706 Downloaded from http://cshperspectives.cshlp.org/ on October 8, 2021 - Published by Cold Spring Harbor Laboratory Press Regulating the SCN Circadian Clockwork medial (shell) subdivisions have been defined identified as encoding a binding partner to on the basis of innervation and neuropeptider- CLOCK proteins in a yeast two-hybrid screen, gic phenotype. Whereas all SCN neurons are whereas the fly paralog, Cycle, was identified by GABAergic, the shell and the core subdivisions mutagenesis. Finally, the genes encoding the show, respectively, localized expression of argi- cryptochromes (Cry1 and Cry2), the second nine vasopressin (AVP) or vasoactive intestinal set of negative regulators in the mammalian peptide (VIP), and gastrin-releasing peptide clock, were originally identified on the basis of (GRP). Anatomical studies have shown that their homology with photolyase DNA repair en- the SCN is densely innervated by retinal axonal zymes. Following the identification of dCry as a projections (Hattar et al. 2006; McNeill et al. circadian photoreceptor in the fly, it was shown 2011), the core subdivision being the principal that CRY1 and CRY2 are essential negative ele- site of direct and indirect retinal innervation. ments of the mammalian feedback loop. The discovery that light-mediated resetting of Notwithstanding the intriguing recent dis- the SCN clock was accompanied by the induced coveries of circadian oscillations in peroxire- expression of immediate-early genes such as cfos doxin superoxidation in transcriptionally in- in the retinorecipient core directed the analysis competent anucleate erythrocytes (see Reddy of circadian timekeeping in mammals toward and Rhee 2016) and the expression of such cy- signal transduction and transcriptional regula- cles in SCN slice culture (Edgar et al. 2012), the tion. These studies involving the conversion of consensus model of how the mammalian clock- light-induced biochemical changes to behavio- work operates at a molecular level involves an ral phase shifts paved the way for subsequent intracellular, autoregulatory, delayed negative interrogation of the molecular genetic basis of feedback model, incorporating transcriptional the clock. and posttranslational feedback loops (TTFLs). In this scheme, early circadian day is marked in the SCN by the initiation of transcriptional A SHORT HISTORY OF THE MAMMALIAN activation of Per and Cry genes mediated by MOLECULAR CLOCKWORK heterodimers of CLOCK and BMAL1 acting The Tau mutant hamster, in which behavioral on “E-box” enhancer sequences (Fig. 2). Over and metabolic cycles free-run with a period of the course of the day, transcript levels increase, 20 hours in homozygotes, illustrated that the accompanied by an increase in the levels of the mammalian clock could be analyzed at a single relevant proteins. Circadian regulation of trans- gene level. Identification of the genetic compo- lational efficiency via mTOR and MAPK signal- nents of the clock came, however, from de novo ing cascades, converging on phosphorylation of gene discovery in mice and by homology with the cap-binding protein eIF4E may facilitate known elements of the Drosophila clockwork this increase, such that by the end of circadian (see Ode 2016). For example, Period1 (Per1), day nuclear complexes of PER and CRY sup- which encodes a negative transcriptional regu- press the activity of CLOCK and BMAL1 (Cao lator within the clock mechanism, was cloned et al. 2013). Crystal structures recently revealed on the basis of conserved sequence identity with that CRY1 binds to a PAS domain within the PASdimerization domains of dPer, but it was CLOCK and a TAD domain within the carboxyl also discovered independently as atranscript en- terminus of BMAL1 to switch off transcrip- coded by human chromosome
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