Cell-autonomous clock of astrocytes drives circadian behavior in mammals

Circadian (~24-hour) rhythms depend on intracellular transcription-translation negative feedback loops (TTFLs). How these self-sustained cellular clocks achieve multicellular integration and thereby direct daily rhythms of behavior in animals is largely obscure. The suprachiasmatic nucleus (SCN) is the fulcrum of this pathway from gene to cell to circuit to behavior in mammals. We describe cell type–specific, functionally distinct TTFLs in neurons and astrocytes of the SCN and show that, in the absence of other cellular clocks, the cell-autonomous astrocytic TTFL alone can drive molecular oscillations in the SCN and circadian behavior in mice. Astrocytic clocks achieve this by reinstating clock gene expression and circadian function of SCN neurons via glutamatergic signals. Our results demonstrate that astrocytes can autonomously initiate and sustain complex mammalian behavior.

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Acute Knockdown of Kv4.1 Regulates Repetitive Firing Rates and Clock Gene Expression in the Suprachiasmatic Nucleus and Daily Rhythms in Locomotor Behavior

eNeuro ◽

10.1523/eneuro.0377-16.2017 ◽

2017 ◽

Vol 4 (3) ◽

pp. ENEURO.0377-16.2017 ◽

Cited By ~ 11

Author(s):

Tracey O. Hermanstyne ◽

Daniel Granados-Fuentes ◽

Rebecca L. Mellor ◽

Erik D. Herzog ◽

Jeanne M. Nerbonne

Keyword(s):

Gene Expression ◽

Suprachiasmatic Nucleus ◽

Clock Gene ◽

Locomotor Behavior ◽

Repetitive Firing ◽

Daily Rhythms ◽

Firing Rates ◽

Clock Gene Expression

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Inducible and Reversible Clock Gene Expression in Brain Using the tTA System for the Study of Circadian Behavior

PLoS Genetics ◽

10.1371/journal.pgen.0030033.eor ◽

2005 ◽

Vol preprint (2007) ◽

pp. e33

Author(s):

Hee-Kyung Hong ◽

Jason L. Chong ◽

Weimin Song ◽

Eun Joo Song ◽

Amira A. Jyawook ◽

...

Keyword(s):

Gene Expression ◽

Clock Gene ◽

Clock Gene Expression ◽

Circadian Behavior

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Inducible and Reversible Clock Gene Expression in Brain Using the tTA System for the Study of Circadian Behavior

PLoS Genetics ◽

10.1371/journal.pgen.0030033 ◽

2007 ◽

Vol 3 (2) ◽

pp. e33 ◽

Cited By ~ 49

Author(s):

Hee-Kyung Hong ◽

Jason L Chong ◽

Weimin Song ◽

Eun Joo Song ◽

Amira A Jyawook ◽

...

Keyword(s):

Gene Expression ◽

Clock Gene ◽

Clock Gene Expression ◽

Circadian Behavior

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Time-lapse confocal imaging of clock gene expression and calcium in neuronal networks of suprachiasmatic nucleus

Neuroscience Research ◽

10.1016/j.neures.2011.07.225 ◽

2011 ◽

Vol 71 ◽

pp. e53

Author(s):

Ryosuke Enoki ◽

Shigeru Kuroda ◽

Daisuke Ono ◽

Tetsuo Ueda ◽

Hasan Mazhir ◽

...

Keyword(s):

Gene Expression ◽

Suprachiasmatic Nucleus ◽

Neuronal Networks ◽

Clock Gene ◽

Time Lapse ◽

Confocal Imaging ◽

Clock Gene Expression

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Dynamics of the Adjustment of Clock Gene Expression in the Rat Suprachiasmatic Nucleus to an Asymmetrical Change from a Long to a Short Photoperiod

Journal of Biological Rhythms ◽

10.1177/0748730407301052 ◽

2007 ◽

Vol 22 (3) ◽

pp. 259-267 ◽

Cited By ~ 11

Author(s):

Alena Sumová ◽

Zuzana Kováčiková ◽

Helena Illnerová

Keyword(s):

Gene Expression ◽

Suprachiasmatic Nucleus ◽

Clock Gene ◽

Short Photoperiod ◽

Clock Gene Expression

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Phase-dependent induction by light of rat Clock gene expression in the suprachiasmatic nucleus

Molecular Brain Research ◽

10.1016/s0169-328x(99)00031-5 ◽

1999 ◽

Vol 66 (1-2) ◽

pp. 104-110 ◽

Cited By ~ 26

Author(s):

Hiroshi Abe ◽

Sato Honma ◽

Masakazu Namihira ◽

Yusuke Tanahashi ◽

Masaaki Ikeda ◽

...

Keyword(s):

Gene Expression ◽

Suprachiasmatic Nucleus ◽

Clock Gene ◽

Clock Gene Expression

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Temporally chimeric mice reveal flexibility of circadian period-setting in the suprachiasmatic nucleus

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.1511351113 ◽

2016 ◽

Vol 113 (13) ◽

pp. 3657-3662 ◽

Cited By ~ 38

Author(s):

Nicola J. Smyllie ◽

Johanna E. Chesham ◽

Ryan Hamnett ◽

Elizabeth S. Maywood ◽

Michael H. Hastings

Keyword(s):

Gene Expression ◽

Suprachiasmatic Nucleus ◽

Feedback Loops ◽

Chimeric Mice ◽

Pacemaker Cells ◽

Daily Behavior ◽

New Perspective ◽

Circadian Behavior

The suprachiasmatic nucleus (SCN) is the master circadian clock controlling daily behavior in mammals. It consists of a heterogeneous network of neurons, in which cell-autonomous molecular feedback loops determine the period and amplitude of circadian oscillations of individual cells. In contrast, circuit-level properties of coherence, synchrony, and ensemble period are determined by intercellular signals and are embodied in a circadian wave of gene expression that progresses daily across the SCN. How cell-autonomous and circuit-level mechanisms interact in timekeeping is poorly understood. To explore this interaction, we used intersectional genetics to create temporally chimeric mice with SCN containing dopamine 1a receptor (Drd1a) cells with an intrinsic period of 24 h alongside non-Drd1a cells with 20-h clocks. Recording of circadian behavior in vivo alongside cellular molecular pacemaking in SCN slices in vitro demonstrated that such chimeric circuits form robust and resilient circadian clocks. It also showed that the computation of ensemble period is nonlinear. Moreover, the chimeric circuit sustained a wave of gene expression comparable to that of nonchimeric SCN, demonstrating that this circuit-level property is independent of differences in cell-intrinsic periods. The relative dominance of 24-h Drd1a and 20-h non-Drd1a neurons in setting ensemble period could be switched by exposure to resonant or nonresonant 24-h or 20-h lighting cycles. The chimeric circuit therefore reveals unanticipated principles of circuit-level operation underlying the emergent plasticity, resilience, and robustness of the SCN clock. The spontaneous and light-driven flexibility of period observed in chimeric mice provides a new perspective on the concept of SCN pacemaker cells.

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Neuron-specific knockouts indicate the importance of network communication to Drosophila rhythmicity

10.1101/639146 ◽

2019 ◽

Cited By ~ 1

Author(s):

M Schlichting ◽

MM Diaz ◽

J Xin ◽

M Rosbash

Keyword(s):

Gene Expression ◽

Circadian Rhythms ◽

Intercellular Communication ◽

Clock Gene ◽

Feedback Loops ◽

Neuronal Firing ◽

Network Communication ◽

Constant Darkness ◽

Circadian Period ◽

Clock Gene Expression

AbstractAnimal circadian rhythms persist in constant darkness and are driven by intracellular transcription-translation feedback loops. Although these cellular oscillators communicate, isolated mammalian cellular clocks continue to tick away in darkness without intercellular communication. To investigate these issues in Drosophila, we assayed behavior as well as molecular rhythms within individual brain clock neurons while blocking communication within the ca. 150 neuron clock network. We also generated CRISPR-mediated neuron-specific circadian clock knockouts. The results point to two key clock neuron groups: loss of the clock within both regions but neither one alone has a strong behavioral phenotype in darkness; communication between these regions also contributes to circadian period determination. Under these dark conditions, the clock within one region persists without network communication. The clock within the famous PDF-expressing s-LNv neurons however was strongly dependent on network communication, likely because clock gene expression within these vulnerable sLNvs depends on neuronal firing or light.

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