Temporal signals drive the emergence of multicellular information networks

TL;DR

This study reveals how external temporal signals influence the formation and connectivity of multicellular information networks in neuronal cells, highlighting the role of stimulus timing and cell communication in network dynamics.

Contribution

It introduces a novel analysis of calcium signaling dynamics, demonstrating how external stimuli shape multicellular networks through causal inference and a theoretical model.

Findings

Network connectivity depends on stimulus temporal profile

Optimal communication strength maximizes network connectivity

External stimuli regulate information transfer in neuronal cells

Abstract

Coordinated responses to environmental stimuli are critical for multicellular organisms. To overcome the obstacles of cell-to-cell heterogeneity and noisy signaling dynamics within individual cells, cells must effectively exchange information with peers. However, the dynamics and mechanisms of collective information transfer driven by external signals is poorly understood. Here we investigate the calcium dynamics of neuronal cells that form confluent monolayers and respond to cyclic ATP stimuli in microfluidic devices. Using Granger inference to reconstruct the underlying causal relations between the cells, we find that the cells self-organize into spatially decentralized and temporally stationary networks to support information transfer via gap junction channels. The connectivity of the causal networks depend on the temporal profile of the external stimuli, where short periods, or long periods with small duty fractions, lead to reduced connectivity and fractured network topology. We build a theoretical model based on communicating excitable units that reproduces our observations. The model further predicts that connectivity of the causal network is maximal at an optimal communication strength, which is confirmed by the experiments. Together, our results show that information transfer between neuronal cells is externally regulated by the temporal profile of the stimuli, and internally regulated by cell-cell communication.