Recurrently connected and localized neuronal communities initiate coordinated spontaneous activity in neuronal networks

Developing neuronal systems intrinsically generate coordinated spontaneous activity that propagates by involving a large number of synchronously firing neurons. In vivo, waves of spikes transiently characterize the activity of developing brain circuits and are fundamental for activity-dependent circuit formation. In vitro, coordinated spontaneous spiking activity, or network bursts (NBs), interleaved within periods of asynchronous spikes emerge during the development of 2D and 3D neuronal cultures. Several studies have investigated this type of activity and its dynamics, but how a neuronal system generates these coordinated events remains unclear. Here, we investigate at a cellular level the generation of network bursts in spontaneously active neuronal cultures by exploiting high-resolution multielectrode array recordings and computational network modelling. Our analysis reveals that NBs are generated in specialized regions of the network (functional neuronal communities) that feature neuronal links with high cross-correlation peak values, sub-millisecond lags and that share very similar structural connectivity motifs providing recurrent interactions. We show that the particular properties of these local structures enable locally amplifying spontaneous asynchronous spikes and that this mechanism can lead to the initiation of NBs. Through the analysis of simulated and experimental data, we also show that AMPA currents drive the coordinated activity, while NMDA and GABA currents are only involved in shaping the dynamics of NBs. Overall, our results suggest that the presence of functional neuronal communities with recurrent local connections allows a neuronal system to generate spontaneous coordinated spiking activity events. As suggested by the rules used for implementing our computational model, such functional communities might naturally emerge during network development by following simple constraints on distance-based connectivity.

发育中的神经元系统可自发产生协同自发放电活动，该活动通过募集大量同步放电神经元进行传播。在活体状态下，锋电位波会短暂成为发育中脑环路活动的标志性特征，且对于依赖活动的环路形成至关重要。在体外培养环境中，二维与三维神经元培养物发育过程中会出现协同自发放电活动——即网络爆发（network bursts, NBs）——该活动与异步放电时段交替出现。
已有多项研究对这类活动及其动力学特性展开了探究，但神经元系统如何产生此类协同活动事件，目前仍未明确。本研究借助高分辨率多电极阵列（multielectrode array, MEA）记录技术与计算网络建模方法，从细胞层面探究了自发放电神经元培养物中网络爆发的产生机制。
分析结果表明，网络爆发产生于神经网络的特定区域——即功能神经元集群（functional neuronal communities），这些区域的神经元连接具有较高的互相关峰值、亚毫秒级时滞，且共享高度相似的结构连接基序以提供循环交互作用。本研究证实，这些局部结构的特殊属性可实现对自发异步锋电位的局部放大，而该机制能够触发网络爆发的启动。
通过对模拟数据与实验数据的分析，本研究还发现：α-氨基-3-羟基-5-甲基-4-异恶唑丙酸受体电流（AMPA currents）可驱动协同活动，而N-甲基-D-天冬氨酸受体电流（NMDA currents）与γ-氨基丁酸受体电流（GABA currents）仅参与调控网络爆发的动力学特性。
综上，本研究结果表明，具备局部循环连接的功能神经元集群的存在，使得神经元系统能够产生自发的协同锋电位活动事件。正如本研究计算模型的实现规则所揭示的那样，这类功能神经元集群或许可在环路发育过程中，通过遵循基于距离的连接的简单约束条件自然形成。