Period Coding of Bmal1 Oscillators in the Suprachiasmatic Nucleus

Myung, Jihwan; Hong, Sungho; Hatanaka, Fumiyuki; Nakajima, Yoshihiro; Schutter, Erik De; Takumi, Toru

doi:10.1523/jneurosci.5586-11.2012

Cited by 67 publications

(135 citation statements)

References 54 publications

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“…S1). The period of the Bmal1-ELuc reporter oscillation in the SCN changes similarly to the change in behavioral period after day-length entrainment (12), similar to Per1 GFP rhythms in cultured SCNs after perinatal photoperiodic imprinting (24). Bioluminescence imaging revealed that the phase distribution of the cellular Bmal1-ELuc oscillations in the SCN becomes narrower after SD and wider after LD entrainment ( Fig.…”

Section: Representation Of Entrained Day Length In the Scn By Networkmentioning

confidence: 55%

“…When measured through a luciferase reporter monitoring oscillations in the Bmal1 gene, the D-SCN and V-SCN clusters show a phase gap, with the D-SCN leading the V-SCN. Although the D-SCN/V-SCN cluster structure is preserved across a moderate range of day length (8-16 h) (12), the phase gap increases with increasing day length (13). The mechanism for this phase gap remains unknown.…”

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confidence: 99%

“…This in-phase state, however, is insufficient to explain the day length-dependent phase gap that is stably seen experimentally (12,13). According to the phase model, a phase gap can result from the difference in period between the D-SCN and the V-SCN; a larger phase gap emerges when the difference in period of the D-SCN and V-SCN increases.…”

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confidence: 99%

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GABA-mediated repulsive coupling between circadian clock neurons in the SCN encodes seasonal time

Myung

Hong

DeWoskin

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

146

229

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The mammalian suprachiasmatic nucleus (SCN) forms not only the master circadian clock but also a seasonal clock. This neural network of ∼10,000 circadian oscillators encodes season-dependent day-length changes through a largely unknown mechanism. We show that region-intrinsic changes in the SCN fine-tune the degree of network synchrony and reorganize the phase relationship among circadian oscillators to represent day length. We measure oscillations of the clock gene Bmal1, at single-cell and regional levels in cultured SCN explanted from animals raised under short or long days. Coupling estimation using the Kuramoto framework reveals that the network has couplings that can be both phase-attractive (synchronizing) and -repulsive (desynchronizing). The phase gap between the dorsal and ventral regions increases and the overall period of the SCN shortens with longer day length. We find that one of the underlying physiological mechanisms is the modulation of the intracellular chloride concentration, which can adjust the strength and polarity of the ionotropic GABA A -mediated synaptic input. We show that increasing daylength changes the pattern of chloride transporter expression, yielding more excitatory GABA synaptic input, and that blocking GABA A signaling or the chloride transporter disrupts the unique phase and period organization induced by the day length. We test the consequences of this tunable GABA coupling in the context of excitation-inhibition balance through detailed realistic modeling. These results indicate that the network encoding of seasonal time is controlled by modulation of intracellular chloride, which determines the phase relationship among and period difference between the dorsal and ventral SCN.day-length encoding | repulsive coupling | SCN | GABA | chloride T he physiological and behavioral rhythms of all life on earth are bound to the Earth's rotational cycle of ∼24 h. This fundamental rhythm is also affected by the planet's slanted rotational axis, which causes seasonal variations in the length of the day. How life has adapted to anticipate this yearly rhythm is still debated.The suprachiasmatic nucleus (SCN), the central circadian (∼24 h) pacemaker in mammals, consists of ∼10,000 "clock" neurons. These single-cell clocks maintain endogenous rhythms by autoregulatory feedback loops of genes including period (Per) and brain and muscle Arnt-like 1 (Bmal1) (1). Although it was speculated that seasonal rhythms might be encoded in a single cell (2), single-cell oscillations remain similar regardless of the seasonal time that the SCN tissue encodes (3). Seasonal timing is thus proposed to be encoded in the network of the SCN (4-7) through spatial reorganization of the relative phases of clocks within individual cells (8-10). Subsets of SCN clocks form phase clusters (11) that map approximately to dorsal (shell, D-SCN) and ventral (core, V-SCN) regions of the SCN. When measured through a luciferase reporter monitoring oscillations in the Bmal1 gene, the D-SCN and V-SCN clusters show a phase gap, ...

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Section: Representation Of Entrained Day Length In the Scn By Networkmentioning

confidence: 55%

mentioning

confidence: 99%

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GABA-mediated repulsive coupling between circadian clock neurons in the SCN encodes seasonal time

Myung

Hong

DeWoskin

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

146

229

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“…During long days, however, SCN cells distribute their phase relationships more widely, so that they are less synchronized in their time of daily peak activity. This coincides with a depolarization in the equilibrium potential for GABA (i.e., chloride) (Myung et al 2012;Farajnia et al 2014). Consequently, GABA signaling has the potential to switch from low-frequency, inhibitory communication to higher-frequency, often excitatory, communication.…”

Section: Role Of Gaba: Modulating Synchrony With the Seasonsmentioning

confidence: 92%

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

Herzog

Hermanstyne

Smyllie

et al. 2017

Cold Spring Harb Perspect Biol

197

171

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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 transcription-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 Na þ drive and nighttime K þ drag. Recent studies exploiting intersectional genetics have started to identify the pacemaking roles of particular neuronal groups in the SCN. They support the idea that timekeeping involves nonlinear and hierarchical computations that create and incorporate timing information 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.W e wake and sleep each day. Hormones reach peak plasma levels at specified times, for example cortisol peaks in the early morning. These, and many other physiological and behavioral, daily rhythms depend on an internal circadian clock, the suprachiasmatic nucleus (SCN) of the hypothalamus. Prior reviews have provided excellent summaries of research progress in the location and function of this body clock (Weaver 1998). This work focuses on recent advances in our understanding of the genetic basis for cell-autonomous generation of circadian time, and how cells within the SCN synchronize their daily rhythms across the circuit to produce a coherent oscillation in neuronal activity. It is these circuit-level emergent properties of the SCN that ultimately direct daily behaviors such as wake and sleep.

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“…Because this approach uses abstract limit cycle oscillators, which are not based on underlying molecular dynamics, the variables and parameters of those models are too abstract to compare with physical quantities. Nonetheless, these abstract models can provide important insight into experimental data on phase relationship of circadian rhythms, such as phase response to external signals [16][17][18], phase entrainment [19][20][21][22], and phase regulation via coupling signal [23][24][25][26]. Furthermore, such models have also been used recently to analyse the phase and amplitude information from circadian time-course data [27,28] and to investigate circadian regulation of other systems (e.g.…”

Section: Introductionmentioning

confidence: 99%

Protein sequestration versus Hill‐type repression in circadian clock models

Kim¹

2016

IET syst. biol.

107

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Circadian (~24hr) clocks are self-sustained endogenous oscillators with which organisms keep track of daily and seasonal time. Circadian clocks frequently rely on interlocked transcriptionaltranslational feedback loops to generate rhythms that are robust against intrinsic and extrinsic perturbations. To investigate the dynamics and mechanisms of the intracellular feedback loops in circadian clocks, a number of mathematical models have been developed. The majority of the models use Hill functions to describe transcriptional repression in a way that is similar to the Goodwin model. Recently, a new class of models with protein sequestration-based repression has been introduced. Here, we discuss how this new class of models differs dramatically from those based on Hill-type repression in several fundamental aspects: conditions for rhythm generation, robust network designs and the periods of coupled oscillators. Consistently, these fundamental properties of circadian clocks also differ among Neurospora, Drosophila, and mammals depending on their key transcriptional repression mechanisms (Hill-type repression or protein sequestration). Based on both theoretical and experimental studies, this review highlights the importance of careful modeling of transcriptional repression mechanisms in molecular circadian clocks.

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Period Coding of Bmal1 Oscillators in the Suprachiasmatic Nucleus

Cited by 67 publications

References 54 publications

GABA-mediated repulsive coupling between circadian clock neurons in the SCN encodes seasonal time

GABA-mediated repulsive coupling between circadian clock neurons in the SCN encodes seasonal time

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

Protein sequestration versus Hill‐type repression in circadian clock models

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