The Functional Connectome Mediating Circadian Synchrony in the Suprachiasmatic Nucleus

Dec 23, 2024bioRxiv : the preprint server for biology

Brain network supporting daily rhythm coordination in the body’s internal clock

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Abstract

Analysis of 3447 hours of clock gene expression from 9011 cells in 17 mice revealed a highly conserved functional connectome within the Suprachiasmatic Nucleus (SCN).

The SCN contains approximately 20,000 neuronal clocks that regulate circadian rhythms.
Functional connectivity within the SCN is organized into dorsomedial and ventrolateral modules.
Most connections among SCN cells are local, but long-range connections exist between ventral cells and both ventral and dorsal SCN cells.
SCN cells can be categorized based on connectivity roles such as signal generators, broadcasters, sinks, or bridges.
VIP neurons were identified as critical hubs for generating circadian signals necessary for synchronizing daily rhythms.
Simulations of inferred SCN networks replicated the characteristic dorsal-to-ventral wave of daily PER2 expression.

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Circadian rhythms in mammals arise from the spatiotemporal synchronization of ~20,000 neuronal clocks in the Suprachiasmatic Nucleus (SCN). While anatomical, molecular, and genetic approaches have revealed diverse cell types and signaling mechanisms, the network wiring that enables SCN cells to communicate and synchronize remains unclear. To overcome the challenges of revealing functional connectivity from fixed tissue, we developed MITE (Mutual Information & Transfer Entropy), an information theory approach that infers directed cell-cell connections with high fidelity. By analyzing 3447 hours of continuously recorded clock gene expression from 9011 cells in 17 mice, we found that the functional connectome of SCN was highly conserved bilaterally and across mice, sparse, and organized into a dorsomedial and a ventrolateral module. While most connections were local, we discovered long-range connections from ventral cells to cells in both the ventral and dorsal SCN. Based on their functional connectivity, SCN cells can be characterized as circadian signal generators, broadcasters, sinks, or bridges. For example, a subset of VIP neurons acts as hubs that generate circadian signals critical to synchronize daily rhythms across the SCN neural network. Simulations of the experimentally inferred SCN networks recapitulated the stereotypical dorsal-to-ventral wave of daily PER2 expression and ability to spontaneously synchronize, revealing that SCN emergent dynamics are sculpted by cell-cell connectivity. We conclude that MITE provides a powerful method to infer functional connectomes, and that the conserved architecture of cell-cell connections mediates circadian synchrony across space and time in the mammalian SCN.

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The Functional Connectome Mediating Circadian Synchrony in the Suprachiasmatic Nucleus

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