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Proc Natl Acad Sci U S A. 2016 Mar 29;113(13):3657-62. doi: 10.1073/pnas.1511351113. Epub 2016 Mar 10.

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

Author information

1
Division of Neurobiology, Medical Research Council Laboratory of Molecular Biology, Cambridge, CB2 0QH United Kingdom.
2
Division of Neurobiology, Medical Research Council Laboratory of Molecular Biology, Cambridge, CB2 0QH United Kingdom mha@mrc-lmb.cam.ac.uk.

Abstract

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.

KEYWORDS:

circuit; entrainment; neuropeptide; oscillator; period

PMID:
26966234
PMCID:
PMC4822582
DOI:
10.1073/pnas.1511351113
[Indexed for MEDLINE]
Free PMC Article

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