Dynamic Interactions Mediated by Nonredundant Signaling Mechanisms Couple Circadian Clock Neurons

Evans, Jennifer; Leise, Tanya; Castanon-Cervantes, Oscar; Davidson, Alec J.

doi:10.1016/j.neuron.2013.08.022

Cited by 184 publications

(302 citation statements)

References 60 publications

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“…High-frequency GABA signals affect the firing of SCN neurons and have been mapped previously (27); however, fast scale GABA is not thought to affect the core oscillator (16). Additionally, due to the limitations of the PER2::LUC bioluminescent reporter used to observe core clock gene expression, the most rapid sampling provides 30-min sample intervals (19), insufficient for methods such as Granger causality (41).…”

Section: Resultsmentioning

confidence: 99%

“…Neurons in the SCN generate circadian oscillations through a transcription-translation feedback loop and are known to synchronize by the timely release of vasoactive intestinal peptide (VIP) and GABA neurotransmitters, which modulate the oscillator through the transcription factor CREB (10,(16)(17)(18)(19). Although the single-cell oscillator and coupling pathways have been extensively researched, relatively little is known about the structure of the neuronal network driving synchronization in the SCN.…”

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confidence: 99%

“…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).…”

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confidence: 99%

“…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). This approach has had great successes in reconciling the roles of GABA and VIP (17,16,19,26). A significant obstacle in developing a mechanistic understanding of synchronization in the SCN is the lack of single-cell resolution in these studies, preventing observation of the dynamics within these clusters.…”

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confidence: 99%

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Functional network inference of the suprachiasmatic nucleus

Abel

Meeker

Granados‐Fuentes

et al. 2016

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

100

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In the mammalian suprachiasmatic nucleus (SCN), noisy cellular oscillators communicate within a neuronal network to generate precise system-wide circadian rhythms. Although the intracellular genetic oscillator and intercellular biochemical coupling mechanisms have been examined previously, the network topology driving synchronization of the SCN has not been elucidated. This network has been particularly challenging to probe, due to its oscillatory components and slow coupling timescale. In this work, we investigated the SCN network at a single-cell resolution through a chemically induced desynchronization. We then inferred functional connections in the SCN by applying the maximal information coefficient statistic to bioluminescence reporter data from individual neurons while they resynchronized their circadian cycling. Our results demonstrate that the functional network of circadian cells associated with resynchronization has small-world characteristics, with a node degree distribution that is exponential. We show that hubs of this small-world network are preferentially located in the central SCN, with sparsely connected shells surrounding these cores. Finally, we used two computational models of circadian neurons to validate our predictions of network structure.

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Section: Resultsmentioning

confidence: 99%

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confidence: 99%

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confidence: 99%

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confidence: 99%

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Functional network inference of the suprachiasmatic nucleus

Abel

Meeker

Granados‐Fuentes

et al. 2016

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

100

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“…After photoperiodic entrainment to a regime of LD20:4, the SCN neurons require neurotransmission by GABA as well as vasoactive intestinal peptide to readjust the phase of their rhythms in PERIOD2 expression (19). We have shown in the present study that the effect of a long-day photoperiod (LD16:8) on the ratio between excitation and inhibition is restricted to the day.…”

Section: Discussionmentioning

confidence: 52%

Seasonal induction of GABAergic excitation in the central mammalian clock

Farajnia

Westering

Meijer

et al. 2014

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

104

129

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The balance between excitation and inhibition is essential for the proper function of neuronal networks in the brain. The inhibitory neurotransmitter γ-aminobutyric acid (GABA) contributes to the network dynamics within the suprachiasmatic nucleus (SCN), which is involved in seasonal encoding. We investigated GABAergic activity and observed mainly inhibitory action in SCN neurons of mice exposed to a short-day photoperiod. Remarkably, the GABAergic activity in a long-day photoperiod shifts from inhibition toward excitation. The mechanistic basis for this appears to be a change in the equilibrium potential of GABA-evoked current. These results emphasize that environmental conditions can have substantial effects on the function of a key neurotransmitter in the central nervous system.S easonal changes in the photoperiod of the Earth's temperate zones affect the behavior and physiology of many organisms (1). The central circadian clock, located in the suprachiasmatic nucleus (SCN) of the anterior hypothalamus, can adapt to changes in day length and displays a compressed circadian pattern of electrical activity in short winter days and a decompressed pattern in long summer days (2). This pattern is based on a change in the phase distribution of the activity patterns of individual neurons, which becomes broad in the summer and narrow in the winter (3). The mechanisms that mediate and regulate photoperiod-induced phase distributions are currently not known.The neurotransmitter γ-aminobutyric acid (GABA) is believed to be involved in the phase adjustment and synchronization of the SCN neuronal network (4, 5). GABA and its receptors are expressed in most SCN neurons (6). GABAergic inhibition has been indicated to be important in normal physiological function within the brain. Alterations in this system (i.e., less inhibition) are shown to cause neurological disorders, such as epilepsy and autism (7,8). In addition to its classical inhibitory function within the SCN network, GABA has more recently been shown to also act as an excitatory transmitter, although its exact role is uncertain (4, 9-13). To understand the influence of photoperiod on GABAergic function, we studied synaptic activity, using patch clamp, and GABAergic responses, using Ca 2+ imaging techniques, in the SCN of mice adjusted to long-day and short-day photoperiods. We hypothesized that the narrow, synchronized phase distribution of active neurons during short-day photoperiods would result in increased synaptic activity during the day. Surprisingly, however, exposure to a short-day photoperiod decreased the frequency of spontaneous GABAergic synaptic events compared with the long-day photoperiod.Subsequently, we tested the effect of photoperiod on GABAinduced excitation in the SCN neuronal network. Ca 2+ transients were measured in response to GABA stimulation in long-day and short-day photoperiods. Interestingly, of all cells from the long-day photoperiod, 40% were excitatory and 36% were inhibitory. In contrast, in the short-day photoperiod, 28% of the c...

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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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Dynamic Interactions Mediated by Nonredundant Signaling Mechanisms Couple Circadian Clock Neurons

Cited by 184 publications

References 60 publications

Functional network inference of the suprachiasmatic nucleus

Functional network inference of the suprachiasmatic nucleus

Seasonal induction of GABAergic excitation in the central mammalian clock

Asymmetric vasopressin signaling spatially organizes the master circadian clock

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