Written by Sun Bo, Li Guanyu

Responsible editor - Wang Sizhen

Editor—Natsuba

Higher animals can perceive and predict regular temporal signals, so can a minimalist system of a group of nerve cells also achieve this function? The various chemicals in the environment in which human cells live are often in a state of flux, so correctly sensing and responding to external environmental stimuli is necessary to maintain the normal survival of multicellular organisms [1, 2
].

Figure 1.
Experimental setup for revealing the potential self-organization of single-layer KTaR cells, overall relative calcium ion intensity changes, and cell network demonstration reconstructed by Granger reasoning

(Source: G Li et al, PNAS, 2022)

First, the authors studied
the changes in the network over two consecutive cycles.

For a directed graph, the connections between two cells inside the network will have no more than the following three changes (Figure 2A): 1.
Existed in the previous cycle and did not exist
in that cycle.

2.
Not present in the previous cycle, not in
that cycle.

3.
Existed in the previous cycle, existed in the current cycle but reversed the direction
.

Therefore, for these three cases, the author defines the corresponding evolution rate1.
P_del 、2.
P_add、3.
P_flp
。
The box plot of Figure 2B shows the change of the three evolution rates under different cycle length stimuli, and it is worth noting that regardless of the period, the probability of the reversal direction of the formed connection is extremely low
.

At the same time, Figure 2C shows that the number of deleted connections and the number of new connections are approximately equal
in each consecutive cycle in the case of different cycle lengths.

Taken together, this means that the variation of this causal network over a continuous period is maintained in dynamic equilibrium: i.
e.
, the directivity of the connection remains unchanged with the total number of connections unchanged (Figure 2).

Figure 2.
The dynamic evolution of multicellular networks under periodic ATP stimulation, a box-shaped plot of the evolutionary probability of three connectivity evolutionary events, and a comparison of increasing and decreasing connection values (Source: G Li et al, PNAS, 2022) Subsequently, as a marker of the intercellular information transfer jump, the authors quantify the connectivity of the network by analyzing the connection probability of the network
.

The connection probability in this article is defined as the ratio
of the number of connections in the network to the number of nearest neighbors (the maximum number of connections that can be established).

Figure 3A shows the change in connectivity caused by random swapping of a smaller number of cells (10%), which shows that the change in cell position has a significant impact on
network connectivity.

This result shows that the cell communication in the experiment in this paper is limited to the peripheral local region of the cell, which further supports the author's inference that cell-to-cell communication is dominated by gap connections (Figure 3A
).

Next, the authors hope to explore the factors
that dominate network connectivity in external stimuli.

In this context, the adjustable external factors are the cycle length of the periodic stimulus and the ATP concentration, both of which represent the temporal distribution of the external stimulus and the chemical intensity
.

The boxplot in Figure 3B shows that the connection probability increases with the length of the cycle, but the change in ATP concentration does not affect the connection probability, from which it can be concluded that network connectivity is dominated by the time distribution of external stimuli rather than chemical intensity (Figure 3B).

Figure 3.
The communication probability of the randomly swapped spatial position network is compared with the original network and the communication probability under different stimulus conditions

(Source: G Li et al, PNAS, 2022)

Finally, the authors and collaborators studied the effect of cell communication degree on the network by comparing the experimental results with theoretical simulations
.

Figure 4.
Experimental data on the model to predict the change of the connection probability with the coupling constant and the connection probability under different cell communication degrees

(Source: G Li et al, PNAS, 2022)

In summary, this paper uses statistical causal test methods to explore the information exchange network existing inside single-layer nerve cells, and finds that under periodic stimulation, single-layer nerve cells can spontaneously form a spatially centralized network, while maintaining dynamic stability
in the network connectivity during continuous cyclical evolution.

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End of article