Review
Cell autonomy and synchrony of suprachiasmatic nucleus circadian oscillators

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The suprachiasmatic nucleus (SCN) of the hypothalamus is the site of the master circadian pacemaker in mammals. The individual cells of the SCN are capable of functioning independently from one another and therefore must form a cohesive circadian network through intercellular coupling. The network properties of the SCN lead to coordination of circadian rhythms among its neurons and neuronal subpopulations. There is increasing evidence for multiple interconnected oscillators within the SCN, and in this review we will highlight recent advances in our knowledge of the complex organization and function of the cellular and network-level SCN clock. Understanding the way in which synchrony is achieved between cells in the SCN will provide insight into the means by which this important nucleus orchestrates circadian rhythms throughout the organism.

Section snippets

The circadian network

Behavioral and physiological processes are coordinated by endogenous biological clocks, permitting organisms to synchronize to and anticipate changes in the environment. The circadian system serves this purpose by generating and sustaining 24 h rhythms of biological processes and by synchronizing to external stimuli such as the solar day–night cycle. In mammals, circadian clocks exist throughout the body, in individual cells and organs, and these clocks are kept synchronized by a master

The SCN

The SCN is a heterogeneous structure [6] (Figure 1). Subregions can be defined throughout the nucleus based on the peptidergic content, the anatomical location, and the circadian parameters of the component cells. Traditionally, the SCN has been divided into two major subdivisions known as the dorsomedial SCN (dmSCN) ‘shell’ and the ventrolateral SCN (vlSCN) ‘core’ 3, 7. The former contains cells expressing arginine vasopressin (AVP); the latter is characterized by expression of vasoactive

Constant light reveals multiple circadian oscillators within the SCN

Perhaps the first evidence that the mammalian circadian system comprises multiple oscillators at the organism level was the observation of ‘splitting’ of locomotor activity rhythms in the ground squirrel (Spermophilus undulatus) [27] and golden hamster (Mesocricetus auratus) [28]. Hamsters housed in constant light display two independent rhythmic components of locomotor activity [28] associated with independently oscillating rhythms of clock gene expression in the right and left SCN 29, 30,

Coupling within the SCN

By contrast to what is observed following jetlag or under conditions of forced desynchrony, the multiple oscillators of the SCN normally function in a unified manner. However, even in the coordinated, intact SCN, cellular oscillations are not completely synchronous. Individual neurons exhibit a range of phases [50]. Heterogeneity of phase can be observed along every anatomical dimension of the SCN [14]. There is a ‘wave’ of oscillatory activity within the SCN 14, 36, 51; expression of Per genes

Network properties confer stability and robustness to the SCN and the circadian system

In addition to maintaining synchrony within SCN neuronal populations, two other important functions of SCN coupling have come to light over the past several years: 1) providing robustness, precision, and stability to SCN rhythms; and 2) generating and sustaining circadian rhythms.

Coupling of SCN neurons leads to robustness (strength and precision of rhythmicity, as well as resistance to perturbation) of the SCN and its output rhythms. As discussed above, the range of periods of individual,

Intercellular signaling plays a role in circadian rhythm generation

Beyond sustaining circadian rhythmicity, there is recent evidence that the network properties of the SCN are capable of generating rhythmicity. Mathematical models have demonstrated that intercellular coupling can sustain rhythmicity in individual cellular oscillators, and experimental evidence supports this prediction 5, 77. Culturing SCN neurons at very low densities results in a substantial decrease (compared to explants or high density cell dispersals) in the number of neurons exhibiting

Mechanisms of intercellular communication within the SCN

The mechanisms by which individual cells in the SCN couple to produce stable, coherent rhythms are not fully understood. As discussed above, blocking sodium-dependent action potentials with TTX 50, 79 or isolating neurons within the SCN [78] leads to cellular desynchrony. This suggests that neurotransmission is vital to the maintenance of circadian rhythmicity, although gap junctions may also play an important role in SCN coupling 80, 81.

Unraveling the SCN network

Intercellular coupling of cell autonomous oscillators within the SCN confers synchrony and robustness on the master circadian pacemaker. Network-level properties convey a stable circadian phase and period at the tissue level to a nucleus comprising intrinsically variable neuronal rhythms. The ability of this complex network to generate rhythmicity on a background of arrhythmicity [79] provides yet more evidence for the importance and intricacy of coupling within the SCN.

Although our knowledge

Acknowledgements

We thank Dr Rae Silver and Dr Nicholas Foley for Figure 3. We also thank Dr Seung-Hee Yoo for helpful discussions. This work was supported by the National Institutes of Health (NIH P50 MH074924 and R01 MH078024 to J.S.T). J.S.T. is an Investigator in the Howard Hughes Medical Institute.

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