The inferred functional connectome underlying circadian synchronization in the mouse suprachiasmatic nucleus

Dec 11, 2025Proceedings of the National Academy of Sciences of the United States of America

The functional connections involved in circadian rhythms in the mouse brain's suprachiasmatic nucleus.

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Abstract

Recording and analyzing 3,290 hours of clock gene expression from 8,261 SCN neurons across 17 mice revealed a highly conserved SCN network.

Circadian rhythms in mammals arise from the synchronization of approximately 20,000 neuronal clocks in the suprachiasmatic nucleus (SCN).
The developed Mutual Information & Transfer Entropy (MITE) framework allows for the inference of directed cell-cell connections from live-cell imaging.
The SCN network is organized into two asymmetrically coupled modules: dorsal and ventral.
Five functional SCN cell types were identified, which operate independently of their neurochemical identity.
Only about 30% of vasoactive intestinal peptide neurons displayed Hub-like connectivity, acting as Generators and Broadcasters of synchrony signals.
Simulations based on MITE-inferred connections accurately reproduced SCN dynamics, including recovery from desynchrony and the daily dorsal-to-ventral phase wave.

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Circadian rhythms in mammals arise from the spatiotemporal synchronization of ~20,000 neuronal clocks in the suprachiasmatic nucleus (SCN). Although anatomical, molecular, and genetic approaches have revealed diverse SCN cell types, how network-level wiring enables their synchronization remains unclear. To overcome the challenges of inferring functional connectivity from fixed tissue, we developed Mutual Information & Transfer Entropy (MITE), an information-theoretic framework to infer directed cell-cell connections with high fidelity from long-term live-cell imaging. Recording and analyzing 3,290 h of clock gene expression from 8,261 SCN neurons across 17 mice, we uncovered a highly conserved, sparse SCN network organized into two asymmetrically coupled modules: dorsal and ventral. Connectivity analyses revealed five functional SCN cell types independent of neurochemical identity. Notably, only ~30% of vasoactive intestinal peptide neurons exhibited Hub-like connectivity, classifying them as Generators and Broadcasters of synchrony signals. Other spatially stereotyped cell types consistently identified as Bridges, Receivers, or Sinks. Simulations based on MITE-inferred connectomes recapitulated emergent SCN dynamics, including recovery from desynchrony and the daily dorsal-to-ventral phase wave of gene expression. Together, these results demonstrate that MITE enables precise mapping of cellular network topology, revealing the circuit logic and key cell types that mediate circadian synchrony across space and time in the mammalian SCN.