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To maintain normal functionality, it is necessary for a multicellular organism to generate robust responses to external temporal signals. However, the underlying mechanisms to coordinate the collective dynamics of cells remain poorly understood. Here, we study the calcium activity of biological neuron networks excited by periodic ATP stimuli. We use micropatterning to control the cells' physical connectivity. We find that whereas isolated cells become more synchronized in their calcium activity at long driving periods, connected cells become less synchronized, despite expressing more gap junctions which enable calcium exchange. To understand this result, we use a mathematical model in which a bifurcation analysis has previously shown coupling-induced desynchronization in an oscillatory network. Using parameters close to this bifurcation but in the excitable regime, we find that this desynchronization persists and can explain the experimental observations. The model further predicts that co-culturing with gap-junction-deficient cells should restore synchronization, which experiments confirm. Combining quantitative experiments, the physical and biological manipulation of cells, and mathematical modeling, our results suggest that cell-to-cell connectivity significantly affects how populations encode an external temporal signal as it slows down: Sparse networks synchronize due to longer entrainment, whereas highly connected networks can desynchronize due to dynamic frustration. Published by the American Physical Society2025 

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 are 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 depends 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. 

Changing salinity in estuaries due to sea level rise and altered rainfall patterns, as a result of climate change, has the potential to influence the interactions of aquatic pollutants as well as to alter their toxicity. From a chemical property point of view, ionic concentration can increase the octanol–water partition coefficient and thus decrease the water solubility of a compound. Biologically, organism physiology and enzyme metabolism are also altered at different salinities with implications for drug metabolism and toxic effects. This highlights the need to understand the influence of salinity on pesticide toxicity when assessing risk to estuarine and marine fishes, particularly considering that climate change is predicted to alter salinity regimes globally and many risk assessments and regulatory decisions are made using freshwater studies. Therefore, we exposed the Inland Silverside (Menidia beryllina) at an early life stage to seven commonly used pesticides at two salinities relevant to estuarine waters (5 PSU and 15 PSU). Triadimefon was the only compound to show a statistically significant increase in toxicity at the 15 PSU LC50. However, all compounds showed a decrease in LC50 values at the higher salinity, and all but one showed a decrease in the LC10 value. Many organisms rely on estuaries as nurseries and increased toxicity at higher salinities may mean that organisms in critical life stages of development are at risk of experiencing adverse, toxic effects. The differences in toxicity demonstrated here have important implications for organisms living within estuarine and marine ecosystems in the Anthropocene as climate change alters estuarine salinity regimes globally.